[001] The present invention relates to inhibitors of endogenous retrovirus(ERV) components, including Env and Gag proteins or fragments thereof, for use in treating a tauopathy, Parkinson’s disease, or ALS (Amyothrophic Lateral Sclerosis). The present invention further relates to inhibitors of receptors which bind HERV Env proteins for use in treating a tauopathy, Parkinson’s disease, or ALS (Amyothrophic Lateral Sclerosis). The present invention further relates to molecules binding to HERV Env and/or Gag proteins, or fragments thereof, or to a nucleic acid molecule encoding said HERV Env and/or Gag proteins, or fragments thereof, for use in diagnosing a tauopathy, Parkinson’s disease, or ALS.

[002] The deposition of intracellular fibrillar phosphorylated Tau in the central nervous system is a pathologic hallmark of a heterogeneous group of at least 20 neurodegenerative diseases, collectively termed tauopathies. These include Alzheimer’s Disease (AD), Cortical Basal Degeneration (CBD), Progressive Supranuclear Palsy (PSP), Pick’s Disease (PiD) and Frontotemporal Dementia with Parkinsonism related to chromosome 17 (FTDP-17) and others (Williams, Intern Med J (2006), 36: 652-660). AD, the most common tauopathy, is characterized by the presence of senile plaques composed of amyloid-b peptide, as well as by the formation of intraneuronal tangles composed of phosphorylated Tau. With a prevalence of approx. 46.8 million AD patients worldwide in 2015 and an estimated number of 131.5 million cases by 2050 due to demographic changes, AD and other tauopathies pose a tremendous social and economic burden to society. Unfortunately, therapeutic strategies are lacking that could halt the disease. Recent approaches that aimed at reducing amyloid-b levels in AD have been unsuccessful, and clinical trials are gradually centering on Tau as the major drug target Congdon et al. , Nat Rev Neurol (2018), 14: 399-415). Tau is a microtubule- stabilizing protein involved in intracellular trafficking (Vershinin et al., PNAS (2007), 87-92). Aberrant Tau aggregation is believed to start locally in specific brain regions, from where Tau pathology spreads to other regions of the brain (Braak et al., Acta Neuropathol (1991), 82: 239-259; Braak et al., Neurobiol Aging (1997), 18: 351-357). Misfolded Tau has been implicated in neuronal loss and disease severity (Nelson et al., J Neuropathol Exp Neurol (2007), 66: 1136-1146). Tau is subject to several posttranslational modifications such as hyperphosphorylation, acetylation or truncation, which can contribute to aberrant Tau polymerization into small oligomers and filaments. Tau aggregates associated with different tauopathies differ in their anatomical distribution, cell tropism, isoform composition and structure (Kovacs, Neuropathol Appl Neurobiol (2015): 41: 3-23).

[003] Several lines of evidence suggest that transcellular spreading of distinct Tau aggregates may underlie the diversity and progression of tauopathies (Goedert, Science (2015), 349: 1255555). For example, in the case of sporadic AD, Tau aggregate spreading has been proposed to cause disease progression from the locus coeruleus to the transentorhinal cortex and finally to hippocampus and surrounding brain regions (Braak et al. , Acta Neuropathol (2011), 121: 589-595). The mechanism of intercellular Tau aggregate transmission is only insufficiently understood. It is possible that so-far unidentified factors contribute to the sequential pathologic Tau spreading pattern and clinical diversity of distinct tauopathies (Braak et al., Neurobiol Aging (1995), 16: 271-278). Increasing evidence argues that extracellular vesicles (EVs) play a prominent role in disseminating aberrant Tau species to neighboring cells. Insoluble Tau was detected in EVs isolated either from cell culture or from patient CSF (Asai et al., Nat Neuroscie (2015), 18: 1584-1593; Saman et al., J Biol Chem (2012), 287: 3842-3849). Although EV-associated Tau represented only a small fraction of released Tau, it showed pathology-dependent phosphorylation at Thr-181 in CSF of AD patients early in disease (Saman, loc. cit. ; Wang et al., Mol Neurodegener (1017), 12: 5; Frost et al., J Biol Chem (2009), 284: 12845-12852). Importantly, both pharmacological inhibition of EV release and disruption of exosomal membranes by sonication successfully halted Tau propagation in recipient cells or in a Tau transgenic mouse model, highlighting the important role of EVs in spreading of Tau pathology (Sama, loc. cit.; Wang, loc. cit.). So far it is unclear how exactly Tau is sorted into EVs and how these EVs target recipient cells.

[004] As Tau pathology correlates better with the degree of cognitive decline in AD patients than with amyloid-b pathology, greater clinical efficacy may be achieved with Tau-based- therapeutic approaches (Nelson, loc. cit.). Current therapeutic interventions aim at reducing Tau expression, the formation of pathogenic Tau seeds or clearing pathogenic Tau. Strategies include reducing Tau expression by antisense oligonucelotides (Guo et al., Acta Neuropathol (2017), 133: 665-704), increasing cellular Tau degradation or reducing Tau posttranslational modifications, using phosphatase activators, kinase inhibitors, acetylation and deglycosylation inhibitors (Congdon, loc. cit.). Tau aggregation inhibitors such as a methylene blue derivative or curcumin so far had limited effects in phase II/ III clinical trials (Congdon, loc. cit.). Likewise, a phase III clinical trial with microtubule stabilizer Davunetide in PSP patients did not result in cognitive improvements (Boxer et al., Lancet Neurol (2014), 13: 676-685). [005] An alternative approach to treating tauopathies is to halt disease progression by targeting the spreading of pathologic Tau throughout the brain. Antibodies against different forms of phosphorylated, oligomeric or misfolded Tau have been shown to modulate Tau pathology in mouse models. For example, passive immunotherapies with Tau specific antibodies were shown to slow progression of Tau pathology in transgenic mice (d’Abramo et al., PLoS One (2013), 8: e62402; Castillo-Carranza et al., J Neurosci (2014), 34: 4260-4272; Yanamandra et al., Neuron (2013), 80: 402-414). However, little is known how anti-Tau antibodies can reduce intracellular neurofibrillary tangle burden (Congdon, loc. cit.). It has been proposed that Tau antibodies achieve therapeutic effects by capturing extracellular Tau and thereby preventing the spreading of Tau pathology. Alternatively, antibodies might also enter neurons and target cytosolic Tau. Several antibodies used in these studies are currently undergoing early clinical trials. A difficulty with Tau-directed antibodies is the insufficient knowledge about the specific type of Tau that causes toxicity and/or is capable of transcellular spreading. Moreover, Tau efficiently spreads via EVs and is thus most likely shielded from extracellular antibody recognition. Consequently, antibodies targeting Tau directly might not be able to terminate the progression of Tau pathology. One way to prevent EV mediated spreading of Tau is to impair efficient transmission of Tau aggregates by targeting EV uptake. The advantage of such approach is that it could impair Tau spreading regardless of the Tau species packaged into EVs. However, very little is known how EVs dock onto target cells and release their cargo into the cytosol.

[006] The gold standard for the diagnosis of tauopathies is still autopsy. Three major tauopathies, PSP, CBD and Pick ^' s disease, are classified based on their characterized neuropathological characteristics. For example, PSP exhibits Tau-positive glial inclusions in the form of "tufted astrocytes" in gray matter; CBD is characterized by typical Tau-positive ballooned neurons and astrocytic deposits; Pick ^' s disease contains Tau-positive "Pick bodies" in neurons. The autopsy diagnosis correlates not well with the syndrome diagnosis. Although CBD and PSP are most commonly associated with CBD clinical syndrome and PSP clinical syndrome, respectively, these syndromes are also shared by other tauopathies. For example, only 50% of cases with CBD clinical syndrome are CBD cases, the rest of cases are diagnosed with AD, PSP, Pick ^' s disease and FTLD-TDP at autopsy (Coughlin et al., Curr Neurol Neurosci Rep (2017), 17: 72). Thus, for specific therapy, it is essential to establish antemortem diagnosis for classification of these tauopathies.

[007] Several different methods have been developed for antemortem diagnosis, including neuroimaging, molecular imaging, and fluid biomarkers. Neuroimaging techniques using MRI proved useful in the diagnosis of PSP with 72.7% specificity but not for other tauopathies (Coughlin, loc. cit.). Molecular imaging, Tau positron emission tomography (PET), has been used in some clinical studies to distinguish AD from control patients. However, the second- generation of Tau specific PET ligands showed very weak binding to pure 3R- or 4R-Tau pathology in post mortem tissue in PSP, CBD and Pick ^' s disease. Moreover, the observed potential off-target binding in susceptible brain regions in PSP and CBD, limits its use in diagnosis of tauopathies that represent with mixtures of 3R- and 4R-Tau pathology (Scholl et al., Mol Cell Neurosci (2018), doi: 10.1016/j.mcn.2018.12.001).

[008] Fluid biomarkers for tauopathies include CSF total Tau and phosphorylated Tau. Total Tau in CSF has been postulated to correlate with neurodegenerative changes in AD patients. However, the increase is not specific for AD and also occurs in other neurodegenerative diseases, such as Creutzfeldt-Jakob disease and brain injury. Phosphorylated Tau in CSF is significantly increased in AD but not in other tauopathies, like PSP. Plasma Tau correlates poorly with CSF Tau levels, which limits its use in the diagnosis of AD (Scholl, loc. cit.). Thus, while determination of phosphorylated Tau levels in CSF in combination with Tau PET imaging could have implications for clinical diagnosis of AD, no suitable ante mortem methods are available for identification of other tauopathies.

[009] Accordingly, the technical problem underlying the present invention was to comply with the disadvantages set out above.

[0010] The present invention addresses the technical problem by providing compounds for use in treating tauopathy, Parkinson’s disease and ALS as set forth herein below and as defined by the claims.

[0011] Accordingly, the present invention relates to an inhibitor of HERV proteins comprising HERV Env and Gag, or a fragment thereof (i.e. fragment of HERV Env and/or HERV Gag protein(s)), for use in treating tauopathies (e.g., Alzheimer’s Disease (AD), Argyrophilic Grain Disease (AGD), Cortical Basal Degeneration (CBD), Progressive Supranuclear Palsy (PSP), Pick’s Disease (PiD), and Frontotemporal Dementia with Parkinsonism related to chromosome 17 (FTDP-17)), Parkinson’s disease, or ALS.

[0012] As surprisingly found in context with the present invention, human endogenous retrovirus (HERV) Env proteins (e.g., from HERV species HERV-W (Syncytin 1), HERV-K, HERV-H, HERV-T, HERV-FRD, HERV-F(c)1, HERV-F(c)2, HERV-E, HERV-P(b1), HERV- VR(b), and HERV-MER34) are upregulated in tauopathies. This applies mutatis mutandis also for HERV Gag proteins given that env and gag mRNA is transcribed together. As has been shown in context with the present invention, there is a correlation between increased HERV Env expression and accelerated intercellular Tau aggregate spreading. Particularly, in accordance with the present invention, ERV Env proteins serve as ligands that mediate the interaction of cellular membranes, resulting in increased transfer of protein aggregate seeds from one cell to another. As shown herein, interruptions of involved ligand-receptor interactions significantly impair the spreading of diverse proteopathic seeds, including Tau aggregates. Furthermore, retroviruses generally depend on proteolytic maturation of the structural protein Gag. Thus, in accordance with the present invention, Env activity is regulated by the maturation status of Gag (cf. Johnson, Nature Reviews Microbiol (2019), 17: 355-370). Without being bound by theory, the maturation of Gag changes the conformation of Gag in the particle and renders Env fusogenic. In other words, again without being bound by theory, in accordance with the present invention, (maturating) Gag activates Env. Accordingly, in context with the present invention, it has surprisingly been found that inhibition of HERV proteins (e.g., inhibition of the maturation or expression of ERV Env and Gag proteins, and/or binding of said ERV Env protein to a receptor; or inhibiting a HERV Env protein receptor from binding the HERV Env protein) is useful for treating tauopathies (e.g., Alzheimer’s Disease (AD), Argyrophilic Grain Disease (AGD), Cortical Basal Degeneration (CBD), Progressive Supranuclear Palsy (PSP), Pick’s Disease (PiD), and Frontotemporal Dementia with Parkinsonism related to chromosome 17 (FTDP-17)). Without being bound by theory, by inhibiting HERV proteins (Env or Gag, or fragments thereof) as described and provided herein, spreading of pathogenic Tau seeds is inhibited or decreased. Also, again without being bound by theory, protein aggregates and the subsequent aggregation of proteins of the same kind in recipient cells is thus inhibited or decreased. Accordingly, in accordance with the present invention, inhibition of HERV proteins (Env or Gag, or fragments thereof) as described and provided herein can also be used for treating associated disorders undelaying such mechanisms such as Parkinson’s disease and ALS (Amyothrophic Lateral Sclerosis).

[0013] As used herein, the term “HERV Env and/or Gag proteins” comprises all types and variants of HERV Env and/or Gag proteins, respectively, including - but not limited to - those Env and Gag proteins of the HERV species HERV-W (Syncytin 1), HER-K, HERV-H, HERV- T, HERV-FRD, HERV-F(c)1, HERV-F(c)2, HERV-E, HERV-P(b1), HERV-R, HERV-R(b), HERV-V and HERV-MER34. In one embodiment of the present invention, specifically those HERV Env and Gag proteins are meant which have been shown to be increased, upregulated or overexpressed in one or more tauopathies, Parkinson’s disease, and/or ALS (Amyothrophic Lateral Sclerosis). [0014] As shown in context with the present invention, HERV transcripts are upregulated in different tauopathies. For example, as has been found in context with the present invention, HERV-W is upregulated in AD patients, while HERV-FRD, -H and -R(b) are associated with CBD disease, and HERV-K and -F(c)1 are increased in PSP patients. Accordingly, in a specific embodiment of the present invention, the HERV Env and/or Gag protein is selected from the group consisting of Env and/or Gag of HERV-W, -FRD, -H, -R(b), -K, and -F(c)1, preferably HERV-W and HERV-K. Accordingly, in one embodiment of the present invention, an inhibitor of a specific HERV Env and/or Gag protein (or fragments thereof) may be particularly useful in treating a specific tauopathy which is associated with upregulation/ increase/ overexpression of the respective HERV Env protein. For example, in accordance with the present invention, an inhibitor of Env and/or Gag (or fragments thereof) from HERV- W may be used for treating AD, an inhibitor of Env and/or Gag (or fragments thereof) from HERV-FRD, -H and/or -R(b) may be used for treating CBD, and an inhibitor of Env and/or Gag (or fragments thereof) from HERV-K and/or -F(c)1 may be used for treating PSP.

[0015] The HERV Env and Gag proteins from HERV-W (Syncytin 1), HER-K, HERV-H, HERV-T, HERV-FRD, HERV-F(c)1, HERV-F(c)2, HERV-E, HERV-P(b1), HERV-R, HERV- R(b), HERV-V and HERV-MER34 are well known in the art.

[0016] For example, in accordance with the present invention, HERV Env proteins (or fragments thereof) as used and described herein may have amino acid sequences encoded by nucleotide sequences being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% identical to those nucleotide sequences shown in SEQ ID NOs. 1 to 13 (particularly Env from HERV-H: SEQ ID NO: 1; HERV-K: SEQ ID NO: 2; HERV-T: SEQ ID NO: 3; HERV-W: SEQ ID NO: 4; HERV-FRD: SEQ ID NO 5; HERV-R: SEQ ID NO: 6; HERV-R(b): SEQ ID NO: 7; HERV-F(c)2: SEQ ID NO: 8; HERV-F(c)1: SEQ ID NO: 9; HERV-E: SEQ ID NO: 10; HERV-P(b1): SEQ ID NO: 11; HERV-V: SEQ ID NO: 12; HERV-MER34: SEQ ID NO: 13). That is, for example, in accordance with the present invention, HERV-H Env as used herein may have an amino acid sequence encoded by a nucleotide sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% identical to the nucleotide sequence shown in SEQ ID NO: 1, and HERV-H Env as used herein may have an amino acid sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% identical to the amino acid sequence shown in SEQ ID NO: 132 to 137, HERV-K Env as used herein may have an amino acid sequence encoded by a nucleotide sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% identical to the nucleotide sequence shown in SEQ ID NO: 2, and HERV-K Env as used herein may have an amino acid sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% identical to the amino acid sequence shown in SEQ ID NO: 101 to 128, HERV-T Env as used herein may have an amino acid sequence encoded by a nucleotide sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% identical to the nucleotide sequence shown in SEQ ID NO: 3, HERV-W Env as used herein may have an amino acid sequence encoded by a nucleotide sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% identical to the nucleotide sequence shown in SEQ ID NO: 4, and HERV-W Env as used herein may have an amino acid sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% identical to the amino acid sequence shown in SEQ ID NO: 129 to 131, HERV-R Env as used herein may have an amino acid sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% identical to the amino acid sequence shown in SEQ ID NO: 138 to 139, and so forth. In this context, preferred are those nucleotide sequences encoding a HERV Env protein as used and described herein which differ from the respective nucleotide sequences of SEQ ID NOs. 1 to 13, respectively, in a manner that any nucleotide difference results only in a conservative or highly conservative amino acid substitution (compared to the amino acid sequences encoded by the nucleotide sequence of the respective SEQ ID NO.), or is silent (i.e. does not translate into an amino acid substitution compared to the amino acid sequences encoded by the nucleotide sequence of the respective SEQ ID NO.).

[0017] As a further example, in accordance with the present invention, HERV Gag proteins (or fragments thereof) as used and described herein may have amino acid sequences encoded by nucleotide sequences being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% identical to those nucleotide sequences shown in SEQ ID NOs. 14 to 21 (particularly Gag from HERV-H: SEQ ID NO: 14; HERV-K (consensus): SEQ ID NO: 15; HERV-K (orico, codon optimized): SEQ ID NO: 16; HERV-T: SEQ ID NO: 17; HERV-W: SEQ ID NO: 18; HERV-R: SEQ ID NO: 19; HERV-E: SEQ ID NO: 20; HERV-V: SEQ ID NO: 21), or have amino acid sequences being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% similar or (preferably) identical to those amino acid sequences shown in SEQ ID NOs. 22 (Gag HERV-F(c)2) to 23 (Gag HERV-F(c)2). That is, for example, in accordance with the present invention, HERV-H Gag as used herein may have an amino acid sequence encoded by a nucleotide sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% identical to the nucleotide sequence shown in SEQ ID NO: 14, HERV-K (consensus) Gag as used herein may have an amino acid sequence encoded by a nucleotide sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% identical to the nucleotide sequence shown in SEQ ID NO: 15, HERV-T Gag as used herein may have an amino acid sequence encoded by a nucleotide sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% identical to the nucleotide sequence shown in SEQ ID NO: 17, HERV-W Gag as used herein may have an amino acid sequence encoded by a nucleotide sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% identical to the nucleotide sequence shown in SEQ ID NO: 18, and so forth. In this context, preferred are those nucleotide sequences encoding a HERV Gag protein as used and described herein which differ from the respective nucleotide sequences of SEQ ID NOs. 14 to 21, respectively, in a manner that any nucleotide difference results only in a conservative or highly conservative amino acid substitution (compared to the amino acid sequences encoded by the nucleotide sequence of the respective SEQ ID NO.), or is silent (i.e. does not translate into an amino acid substitution compared to the amino acid sequences encoded by the nucleotide sequence of the respective SEQ ID NO.). Likewise, preferred are those HERV Gag proteins as used and described herein having amino acid sequences which differ from the respective amino acid sequences of SEQ ID NOs. 22 to 23, respectively, in a manner that only in a conservative or highly conservative amino acid substitutions/insertions/additions/deletions appear (compared to the amino acid sequences of the respective SEQ ID NO.).

[0018] Likewise, as used herein and in accordance with the present invention, HERV Env proteins as used and described herein may have amino acid sequences being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% similar or identical to those amino acid sequences encoded by nucleotide sequences shown in SEQ ID NOs. 1 to 13 (particularly Envs from HERV-H: SEQ ID NO: 1; HERV-K: SEQ ID NO: 2; HERV-T: SEQ ID NO: 3; HERV-W: SEQ ID NO: 4; HERV-FRD: SEQ ID NO 5; HERV-R: SEQ ID NO: 6; HERV-R(b): SEQ ID NO: 7; HERV-F(c)2: SEQ ID NO: 8; HERV-F(c)1: SEQ ID NO: 9; HERV-E: SEQ ID NO: 10; HERV-P(b1): SEQ ID NO: 11; HERV-V: SEQ ID NO: 12; HERV- MER34: SEQ ID NO: 13). That is, for example, in accordance with the present invention, HERV-H Env as used herein may have an amino acid sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% similar or identical to the amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO: 1, HERV-K Env as used herein may have an amino acid sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% similar or identical to the amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO: 2, HERV-T Env as used herein may have an amino acid sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% similar or identical to the amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO: 3, HERV- W Env as used herein may have an amino acid sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% similar or identical to the amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO: 4, and so forth.

[0019] Likewise, as used herein and in accordance with the present invention, HERV Gag proteins as used and described herein may have amino acid sequences being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% similar or identical to those amino acid sequences encoded by nucleotide sequences shown in SEQ ID NOs. 14 to 21 (particularly Gag from HERV-H: SEQ ID NO: 14; HERV-K (consensus): SEQ ID NO: 15; HERV-K (orico, codon optimized): SEQ ID NO: 16; HERV-T: SEQ ID NO: 17; HERV-W: SEQ ID NO: 18; HERV-R: SEQ ID NO: 19; HERV-E: SEQ ID NO: 20; HERV-V: SEQ ID NO: 21). That is, for example, in accordance with the present invention, HERV-H Gag as used herein may have an amino acid sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% similar or identical to the amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO: 14, HERV-K (consensus) Gag as used herein may have an amino acid sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% similar or identical to the amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO: 15, HERV-T Gag as used herein may have an amino acid sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% similar or identical to the amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO: 17, HERV-W Gag as used herein may have an amino acid sequence being at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.8%, or 100% similar or identical to the amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO: 18, and so forth.

[0020] In accordance with the present invention, as used herein in context with amino acid sequences, the term “similar” means that a given amino acid sequence comprises identical amino acids or only conservative or highly conservative substitutions compared to the amino acid sequence of the respective SEQ ID NO. As used herein, “conservative” substitutions mean substitutions as listed as “Exemplary Substitutions” in Table I herein. “Highly conservative” substitutions as used herein mean substitutions as shown under the heading “Preferred Substitutions” in Table I herein.

TABLE I Amino Acid Substitutions

[0021] As used herein, unless specifically defined otherwise, the term “nucleic acid” or “nucleic acid molecule” is used synonymously with “oligonucleotide”, “nucleic acid strand”, or the like, and means a polymer comprising one, two, or more nucleotides. In this context, also the term “target sequence” as used herein comprises nucleic acid molecules.

[0022] As used herein, “silent” mutations mean base substitutions within a nucleic acid sequence which do not change the amino acid sequence encoded by the nucleic acid sequence. “Conservative” substitutions mean substitutions as listed as “Exemplary Substitutions” in Table I. “Highly conservative” substitutions as used herein mean substitutions as shown under the heading “Preferred Substitutions” in Table I.

[0023] The term "position" when used in accordance with the present invention means the position of an amino acid within an amino acid sequence depicted herein. The term "corresponding" in this context also includes that a position is not only determined by the number of the preceding nucleotides/amino acids.

[0024] The level of identity between two or more sequences (e.g., nucleic acid sequences or amino acid sequences) can be easily determined by methods known in the art, e.g., by BLAST analysis. Generally, in context with the present invention, if two sequences (e.g., polynucleotide sequences or amino acid sequences) to be compared by, e.g., sequence comparisons differ in identity, then the term "identity" may refer to the shorter sequence and that part of the longer sequence that matches said shorter sequence. Therefore, when the sequences which are compared do not have the same length, the degree of identity may preferably either refer to the percentage of nucleotide residues in the shorter sequence which are identical to nucleotide residues in the longer sequence or to the percentage of nucleotides in the longer sequence which are identical to nucleotide sequence in the shorter sequence. In this context, the skilled person is readily in the position to determine that part of a longer sequence that matches the shorter sequence. Furthermore, as used herein, identity levels of nucleic acid sequences or amino acid sequences may refer to the entire length of the respective sequence and is preferably assessed pair-wise, wherein each gap is to be counted as one mismatch. These definitions for sequence comparisons (e.g., establishment of "identity" values) are to be applied for all sequences described and disclosed herein.

[0025] Moreover, the term “identity” as used herein means that there is a functional and/or structural equivalence between the corresponding sequences. Nucleic acid/amino acid sequences having the given identity levels to the herein-described particular nucleic acid/amino acid sequences may represent derivatives/variants of these sequences which, preferably, have the same biological function. They may be either naturally occurring variations, for instance sequences from other varieties, species, etc., or mutations, and said mutations may have formed naturally or may have been produced by deliberate mutagenesis. Furthermore, the variations may be synthetically produced sequences. The variants may be naturally occurring variants or synthetically produced variants, or variants produced by recombinant DNA techniques. Deviations from the above-described nucleic acid sequences may have been produced, e.g., by deletion, substitution, addition, insertion and/or recombination. The term "addition" refers to adding a nucleic acid residue/amino acid to the beginning or end of the given sequence, whereas "insertion" refers to inserting a nucleic acid residue/amino acid within a given sequence. The term "deletion" refers to deleting or removal of a nucleic acid residue or amino acid residue in a given sequence. The term "substitution" refers to the replacement of a nucleic acid residue/amino acid residue in a given sequence. Again, these definitions as used here apply, mutatis mutandis, for all sequences provided and described herein.

[0026] Generally, as used herein, the terms ..polynucleotide” and ..nucleic acid” or ..nucleic acid molecule” are to be construed synonymously. Generally, nucleic acid molecules may comprise inter alia DNA molecules, RNA molecules, oligonucleotide thiophosphates, substituted ribo-oligonucleotides or PNA molecules. Furthermore, the term "nucleic acid molecule" may refer to DNA or RNA or hybrids thereof or any modification thereof that is known in the art (see, e.g., US 5525711, US 471 1955, US 5792608 or EP 302175 for examples of modifications). The polynucleotide sequence may be single- or double- stranded, linear or circular, natural or synthetic, and without any size limitation. For instance, the polynucleotide sequence may be genomic DNA, cDNA, mitochondrial DNA, mRNA, antisense RNA, ribozymal RNA or a DNA encoding such RNAs or chimeroplasts (Gamper, Nucleic Acids Research, 2000, 28, 4332 - 4339). Said polynucleotide sequence may be in the form of a vector, plasmid or of viral DNA or RNA. Also described herein are nucleic acid molecules which are complementary to the nucleic acid molecules described above and nucleic acid molecules which are able to hybridize to nucleic acid molecules described herein. A nucleic acid molecule described herein may also be a fragment of the nucleic acid molecules in context of the present invention. Particularly, such a fragment is a functional fragment. Examples for such functional fragments are nucleic acid molecules which can serve as primers.

[0027] The term "amino acid" or "amino acid residue" as used herein typically refers to an amino acid having its art recognized definition such as an amino acid selected from the group consisting of: alanine (Ala or A); arginine (Arg or R); asparagine (Asn or N); aspartic acid (Asp or D); cysteine (Cys or C); glutamine (Gin or Q); glutamic acid (Glu or E); glycine (Gly or G); histidine (His or H); isoleucine (He or I): leucine (Leu or L); lysine (Lys or K); methionine (Met or M); phenylalanine (Phe or F); pro line (Pro or P); serine (Ser or S); threonine (Thr or T); tryptophan (Trp or W); tyrosine (Tyr or Y); and valine (Val or V), although modified, synthetic, or rare amino acids may be used as desired. Generally, amino acids can be grouped as having a nonpolar side chain (e.g., Ala, Cys, He, Leu, Met, Phe, Pro, Val); a negatively charged side chain (e.g., Asp, Glu); a positively charged sidechain

IB (e.g., Arg, His, Lys); or an uncharged polar side chain (e.g., Asn, Cys, Gin, Gly, His, Met, Phe, Ser, Thr, Trp, and Tyr).

[0028] As has been shown in context with the present invention, inhibitors that block maturation of HERV Env proteins also impair spreading of pathogenic aggregates. The same applies mutatis mutandis for inhibitors of HERV Gag protein maturation as this inhibits activation of Env as described above. Ways of inhbiting processing/ maturation of Env or Gag proteins are generally known in the art; cf. Freed, Nature Review Microbiol (2015), 13: 484-496; Tedbury et al., Curr Topics Microbiol and Immunol (2015), 389: 171-201; Venanzi Rullo et al., Mol Med Reports (2019), 19: 1987-1995; Waheed et al., AIDS Res Human Retroviruses (2012), 28: 54-75. Accordingly, in one embodiment of the present invention, in context with the inhibitor of HERV Env and/or Gag proteins (or fragments thereof) as described and provided herein, HERV Env and/or Gag proteins (or fragments thereof) can be inhibited by inhibiting maturation of the respective HERV Env and/or Gag protein (or fragments thereof). Accordingly, in this embodiment of the present invention, the inhibitor of HERV Env and/or Gag proteins may inhibit maturation of the respective HERV Env and/or Gag protein (or fragments thereof). In a specific embodiment of the present invention, the inhibitor of HERV Env and/or Gag proteins (or fragments thereof) inhibits maturation of the respective HERV proteins, wherein said inhibitor is a HERV protease inhibitor which inhibits the respective protease which processes the respective Env or Gag protein for maturation. Due to the similarity to other retroviral gene products (e.g., those of HIV), protease inhibitors which are applied or applicable for treating HIV may also be used in accordance with the present invention to inhibit HERV Env and/or Gag protein (or fragments thereof) for use in treating tauopathy (e.g., Alzheimer’s Disease (AD), Argyrophilic Grain Disease (AGD), Cortical Basal Degeneration (CBD), Progressive Supranuclear Palsy (PSP), Pick’s Disease (PiD), and Frontotemporal Dementia with Parkinsonism related to chromosome 17 (FTDP- 17)), Parkinson’s disease and ALS as described herein. Accordingly, in a specific embodiment of the present invention, the inhibitor of HERV Env and/or Gag proteins (or fragments thereof) may be an HIV-1 retroviral protease inhibitor, e.g., a (HERV) protease inhibitor selected from the group consisting of amprenavir, lopinavir, darunavir, indinavir, atazanavir, fosamprenavir, nelfinavir, ritonavir, saquinavir, and tipranavir, preferably amprenavir and atazanavir. Envisaged herein is a (HERV) protease inhibitor for use in treating Tauopathy, or Parkinson’s disease. Said protease inhibitor may be any one of amprenavir, lopinavir, darunavir, indinavir, atazanavir, fosamprenavir, nelfinavir, ritonavir, saquinavir, tipranavir, amprenavir or atazanavir, preferably amprenavir, atazanavir, or lopinavir. [0029] In accordance with the present invention, the inhibitor of HERV Env and/or Gag proteins (or fragments thereof) as described and provided herein may also be an inhibitor of expression of respective HERV Env and/or Gag proteins. For example, it may inhibit transcription or translation of the HERV Env and/or Gag genes or mRNAs, respectively. Accordingly, in one embodiment of the present invention, the inhibitors of HERV Env and/or Gag proteins as described and provided herein are nucleic acid molecules hybridizing or being complementary to at least a portion of the nucleic acid sequence encoding said HERV Env and/or Gag proteins, thereby inhibiting or preventing transcription or translation of the nucleic acid molecules encoding the HERV Env and/or Gag proteins. In context with the present invention, a suitable nucleic acid molecule for inhibiting expression (e.g., transcription or translation) of a HERV Env and/or Gag protein may be a small interference RNA (siRNA), microRNA (miRNA, miR), Tough Decoys (TuD) (e.g., Tough Decoy RNA), Decoys, antisense oligonucleotides (antisense RNA or DNA, chimeric antisense molecules), ribozymes, external guide sequence (EGS), oligonucleotides, small temporal RNA (stRNA), short hairpin RNA (shRNA), small RNA-induced gene activation (RNAa), small activating RNA (saRNA), locked nucleic acids (LNA), antagomirs, aptamers (DNA, RNA, XNA), peptide nucleic acids (PNA), and other oligomeric nucleic acid molecules, which are able to inhibit or suppress the expression (e.g., transcription or translation) of the nucleic acid molecule encoding the respective HERV Env and/or Gag proteins(e.g., by hybridizing to at least a portion of the nucleic acid molecule encoding the respective HERV Env and/or Gag proteins).

[0030] As used herein, an inhibitor hybridizing or being complementary to “at least a portion” of the nucleic acid sequence encoding said HERV Env protein means that said inhibitor (preferably itself being a nucleic acid molecule as described above) hybridizes or is complementary to at least about 3, 4, 5, 6, 7, 8, 9, 20, 11, 12, 13, 14 or 15 (preferably consecutive) nucleotides of the nucleotide sequence of the respective HERV Env protein (e.g., gene or transcribed mRNA thereof). For example, such inhibitor hybridizes or is complementary to at least about 3, 4, 5, 6, 7, 8, 9, 20, 11, 12, 13, 14 or 15 (preferably consecutive) nucleotides of a nucleotide sequence shown in any one of SEQ ID NOs. 1 to 13 (particularly HERV-H: SEQ ID NO: 1; HERV-K: SEQ ID NO: 2; HERV-T: SEQ ID NO: 3; HERV-W: SEQ ID NO: 4; HERV-FRD: SEQ ID NO 5; HERV-R: SEQ ID NO: 6; HERV-R(b): SEQ ID NO: 7; HERV-F(c)2: SEQ ID NO: 8; HERV-F(c)1: SEQ ID NO: 9; HERV-E: SEQ ID NO: 10; HERV-P(b1): SEQ ID NO: 11; HERV-V: SEQ ID NO: 12; HERV-MER34: SEQ ID NO: 13). That is, for example, in accordance with this embodiment of the present invention, an inhibitor (preferably itself being a nucleic acid molecule as described above) of HERV-H hybridizes or is complementary to at least about 3, 4, 5, 6, 7, 8, 9, 20, 11, 12, 13, 14 or 15 (preferably consecutive) nucleotides of the nucleotide sequence of SEQ ID NO: 1, an inhibitor (preferably itself being a nucleic acid molecule as described above) of HERV-K hybridizes or is complementary to at least about 3, 4, 5, 6, 7, 8, 9, 20, 11, 12, 13, 14 or 15 (preferably consecutive) nucleotides of the nucleotide sequence of SEQ ID NO: 2, an inhibitor (preferably itself being a nucleic acid molecule as described above) of HERV-T hybridizes or is complementary to at least about 3, 4, 5, 6, 7, 8, 9, 20, 11, 12, 13, 14 or 15 (preferably consecutive) nucleotides of the nucleotide sequence of SEQ ID NO: 3, an inhibitor (preferably itself being a nucleic acid molecule as described above) of HERV-W hybridizes or is complementary to at least about 3, 4, 5, 6, 7, 8, 9, 20, 11, 12, 13, 14 or 15 (preferably consecutive) nucleotides of the nucleotide sequence of SEQ ID NO: 4, and so forth. The same applies mutatis mutandis with respect to the Gag HERV proteins encoded by nucleotide sequences corresponding to SEQ ID NOs. 14 to 21 as set forth herein, as well as to Gag HERV proteins having amino acids corresponding to SEQ ID NOs. 22 and 23. In specific examples of the present invention, an inhibitor of a HERV Env protein may have a nucleotide sequence according to any one of SEQ ID NOs. 42-72 (upper letters; corresponding to the respective HERV species as indicated below), wherein up to 3, 2, 1, or (preferably) 0 nucleotides are added, inserted, substituted or deleted compared to said respective nucleotide sequences of SEQ ID NOs. 42-72. Further examples of inhibitors of a HERV Env protein may have a nucleotide sequence according to any one of the murine RNAs shown in SEQ ID NOs: 25-29, wherein up to 3, 2, 1, or (preferably) 0 nucleotides are added, inserted, substituted or deleted compared to said respective nucleotide sequences of SEQ ID NOs: 25 to 29. Additionally, SEQ ID NO: 98 may be another example of such an inhibitor with a loop sequence capable of silencing syncytin-1.

[0031] It is apparent from the abovemetioned, that the HERV Gag protein may be encoded by a nucleotide sequence shown in any one of SEQ ID NOs: 14 to 21, or encoded by a nucleotide sequence that has at least about 85% sequence identity to any one of SEQ ID NOs: 14 to 21. Thus, a nucleic acid molecule hybridizing to at least a portion of the nucleotide sequence of HERV Gag as shown in any one of SEQ ID NOs: 14 to 21, is envisaged herein and may be used for treating Tauopathy, or Parkinson’s disease. Further examples of a nucleic acid molecule may comprise any one of the nucleotide sequence shown in any one of SEQ ID NOs: 30 to 35 which may be use for treating Tauopathy, or Parkinson’s disease.

[0032] The term "hybridization", “hybridizing” or "hybridizes" as used herein in context of nucleic acid molecules/DNA or RNA sequences may relate to hybridizations under stringent or non-stringent conditions. If not further specified, the conditions are preferably non- stringent. Said hybridization conditions may be established according to conventional protocols described, for example, in Sambrook, Russell "Molecular Cloning, A Laboratory Manual", Cold Spring Harbor Laboratory, N. Y. (2001); Current Protocols in Molecular Biology, Update May 9, 2012, Print ISSN: 1934-3639, Online ISSN: 1934-3647; Ausubel, "Current Protocols in Molecular Biology", Green Publishing Associates and Wiley Interscience, N. Y. (1989), or Higgins and Hames (Eds.) "Nucleic acid hybridization, a practical approach" IRL Press Oxford, Washington DC, (1985). The setting of conditions is well within the skill of the artisan and can be determined according to protocols described in the art. Thus, the detection of only specifically hybridizing sequences will usually require stringent hybridization and washing conditions such as 0.1 x SSC, 0.1 % SDS at 65 °C. Non- stringent hybridization conditions for the detection of homologous or not exactly complementary sequences may be set at 6 x SSC, 1% SDS at 65 °C. As is well known, the length of the probe and the composition of the nucleic acid to be determined constitute further parameters of the hybridization conditions. Variations in the above conditions may be accomplished through the inclusion and/or substitution of alternate blocking reagents used to suppress background in hybridization experiments. Typical blocking reagents include Denhardt's reagent, BLOTTO, heparin, denatured salmon sperm DNA, and commercially available proprietary formulations. The inclusion of specific blocking reagents may require modification of the hybridization conditions described above, due to problems with compatibility. In accordance to the invention described herein, low stringent hybridization conditions for the detection of homologous or not exactly complementary sequences may, for example, be set at 6 x SSC, 1% SDS at 65 °C. As is well known, the length of the probe and the composition of the nucleic acid to be determined constitute further parameters of the hybridization conditions.

[0033] Hybridizing nucleic acid molecules also comprise fragments of the above described molecules. Such fragments may represent nucleic acid molecules which code for a functional aaRS as described herein or a functional fragment thereof which can serve as a primer. Furthermore, nucleic acid molecules which hybridize with any of the aforementioned nucleic acid molecules also include complementary fragments, derivatives and variants of these molecules. Additionally, a hybridization complex refers to a complex between two nucleic acid sequences by virtue of the formation of hydrogen bonds between complementary G and C bases and between complementary A and T bases; these hydrogen bonds may be further stabilized by base stacking interactions. The two complementary nucleic acid sequences hydrogen bond in an antiparallel configuration. A hybridization complex may be formed in solution (e.g., Cot or Rot analysis) or between one nucleic acid sequence present in solution and another nucleic acid sequence immobilized on a solid support (e.g., membranes, filters, chips, pins or glass slides to which, e.g., cells have been fixed). The terms complementary or complementarity refer to the natural binding of polynucleotides under permissive salt and temperature conditions by base-pairing. For example, the sequence "A-G-T" binds to the complementary sequence "T-C-A". Complementarity between two single-stranded molecules may be "partial", in which only some of the nucleic acids bind, or it may be complete when total complementarity exists between single-stranded molecules. The degree of complementarity between nucleic acid strands has significant effects on the efficiency and strength of hybridization between nucleic acid strands. This is of particular importance in amplification reactions, which depend upon binding between nucleic acids strands. The term "hybridizing sequences" preferably refers to sequences which display a sequence identity of at least 45%, more preferably at least 50%, more preferably at least 55%, more preferably at least 60%, more preferably at least 65%, more preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98% more preferably at least 99%, more preferably at least 99,5%, and most preferably 100% identity with a nucleic acid sequence as described herein encoding an aaRS as described and provided herein.

[0034] In accordance with the present invention, the inhibitor of HERV Env proteins as described and provided herein may also be an inhibitor of binding of said HERV Env protein to a receptor of said HERV Env protein. As used herein, such receptors of HERV Env proteins generally comprise any receptor for which a HERV Env protein as used and described herein may be a natural ligand, or to which a HERV Env protein as used and described herein binds to with specific affinity. Typically, as generally used herein unless specified otherwise, binding is considered “specific” when the binding affinity is higher than 10 ⁶ M. Preferably, as generally used herein unless specified otherwise, binding is considered specific when binding affinity is about 10 ¹¹ to 10 ⁸ M (K _D ), preferably of about 10 ¹¹ to 10 ⁹ M. If necessary, nonspecific binding can be reduced without substantially affecting specific binding by varying the binding conditions. Whether the recognition molecule specifically reacts as defined herein above can easily be tested, inter alia, by comparing the reaction of said recognition molecule with an epitope with the reaction of said recognition molecule with (an) other protein(s). In accordance with the present invention, non-limiting examples for receptors for HERV Env proteins, e.g., for HERV-W, comprise ASCT1 (gene: SLC1A4) or ASCT2 (gene: SLC1A5). A further possible receptor of HERV-K Env may be a complex of CD98HC and LAT1, as recent studies suggested. This complex may serve as another example of an HERV-K Env receptor.

[0035] In context with the present invention, binding of a HERV Env protein as used and described herein to a corresponding HERV Env protein receptor as described herein can be inhibited by any binding agent either (specifically) binding the respective HERV Env protein, or the corresponding HERV Env protein receptor. In accordance with the present invention, non-limiting examples for such binding agents binding to HERV Env protein or to its respective receptor comprise antibodies, protein aptamers, affimers, small compounds (e.g., those blocking the binding center of a HERV Env receptor), etc.

[0036] In one embodiment of the present invention, the inhibitor of Env protein is an antibody (specifically) binding to a respective Env protein as used and described herein. Preferably, such antibody thus inhibits binding of the respective Env protein to a receptor of the Env protein. In another embodiment of the present invention, the inhibitor is a binding agent as defined herein (e.g., an antibody) (specifically) binding to a receptor of a respective HERV Env protein as used and described herein. Preferably, such antibody thus inhibits binding of a respective HERV Env protein to the receptor of the HERV Env protein.

[0037] Accordingly, the present invention further relates to an inhibitor of a receptor binding a HERV Env protein as used and described herein for use in treating tauopathy (e.g., Alzheimer’s Disease (AD), Argyrophilic Grain Disease (AGD), Cortical Basal Degeneration (CBD), Progressive Supranuclear Palsy (PSP), Pick’s Disease (PiD), and Frontotemporal Dementia with Parkinsonism related to chromosome 17 (FTDP-17)), Parkinson’s disease and ALS. In context with the present invention, in one example, such inhibitor of a HERV Env receptor may be a binding agent (e.g., antibody) as described herein (thereby inhibiting binding of a respective HERV Env protein to the receptor of the HERV Env protein), for example an antibody (specifically) binding to said HERV Env protein receptor. In another example of the present invention, the HERV Env protein receptor inhibitor may inhibit the expression (e.g., transcription or translation) of the HERV Env protein receptor as described herein. For example, it may inhibit transcription or translation of the HERV Env receptor gene or mRNA, respectively. Accordingly, in one embodiment of the present invention, the inhibitor of HERV Env protein receptor as described and provided herein is a nucleic acid molecule hybridizing or being complementary to at least a portion of the nucleic acid sequence encoding said HERV Env protein receptor, thereby inhibiting or preventing transcription or translation of the nucleic acid molecule encoding the HERV Env protein receptor. In context with the present invention, a suitable nucleic acid molecule for inhibiting expression (e.g., transcription or translation) of a HERV Env protein receptor may be a small interference RNA (siRNA), microRNA (miRNA, miR), Tough Decoys (TuD) (e.g., Tough Decoy RNA), Decoys, antisense oligonucleotides (antisense RNA or DNA, chimeric antisense molecules), ribozymes, external guide sequence (EGS), oligonucleotides, small temporal RNA (stRNA), short hairpin RNA (shRNA), small RNA-induced gene activation (RNAa), small activating RNA (saRNA), locked nucleic acids (LNA), antagomirs, aptamers (DNA, RNA, XNA), peptide nucleic acids (PNA), and other oligomeric nucleic acid molecules, which are able to inhibit or suppress the expression (e.g., transcription or translation) of the nucleic acid molecule encoding the respective HERV Env protein receptor (e.g., by hybridizing to at least a portion of the nucleic acid molecule encoding the respective HER Env protein receptor).

[0038] As used herein, an inhibitor hybridizing or being complementary to “at least a portion” of the nucleic acid sequence encoding said HERV Env protein receptor means that said inhibitor (preferably itself being a nucleic acid molecule as described above) hybridizes or is complementary to at least about 3, 4, 5, 6, 7, 8, 9, 20, 11, 12, 13, 14 or 15 (preferably consecutive) nucleotides of the nucleotide sequence of the respective HERV Env protein receptor (e.g., gene or transcribed mRNA thereof).

[0039] Generally, as used herein, such receptors of HERV Env proteins comprise any receptor for which a HERV Env protein as used and described herein may be a natural ligand, or to which a HERV Env protein as used and described herein binds to with specific affinity. In accordance with the present invention, non-limiting examples for receptors for HERV Env proteins, e.g., for HERV-W, comprise SLC1A4 or SLC1A5. Accordingly, in a specific embodiment of the present invention, the HERV Env protein receptor is selected from the group consisting of SLC1A4 and SLC1A5 (Lavillette et al., J Virol (2002), 76: 6442- 6452; and Marin et al., J Virol (2003), 77: 2936-2945). In this context, an inhibitor of SLC1A4 or SLC1A5 may be particularly useful in treating tauopathies.

[0040] The term “antibody” as used herein may be a protein comprising one or more polypeptides (comprising one or more binding domains, preferably antigen binding domains) substantially or partially encoded by immunoglobulin genes or fragments of immunoglobulin genes. The term "immunoglobulin" (Ig) is used interchangeably with "antibody" herein. The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as myriad immunoglobulin variable region genes.

[0041] In particular, an “antibody” when used herein, may comprise tetrameric glycosylated proteins composed of two light (L) chains of approximately 25 kDa each and two heavy (H) chains of approximately 50 kDa each. Two types of light chain, termed lambda and kappa, may be found in antibodies. Depending on the amino acid sequence of the constant domain of heavy chains, immunoglobulins can be assigned to five major classes: A, D, E, G, and M, and several of these may be further divided into subclasses (isotypes), e.g., lgG1, lgG2, lgG3, lgG4, lgA1, and lgA2. An IgM antibody consists of 5 of the basic heterotetramer unit along with an additional polypeptide called a J chain, and contains 10 antigen binding sites, while IgA antibodies comprise from 2-5 of the basic 4-chain units which can polymerize to form polyvalent assemblages in combination with the J chain. In the case of IgGs, the 4- chain unit comprises in most cases about 150,000 daltons.

[0042] Each light chain includes an N-terminal variable (V) domain (VL) and a constant (C) domain (CL). Each heavy chain includes an N-terminal V domain (VH), three or four C domains (CHs), and a hinge region. The constant domains are not involved directly in binding an antibody to an antigen.

[0043] The pairing of a VH and VL together forms a single antigen-binding site. The CH domain most proximal to VH is designated as CH1. Each L chain is linked to an H chain by one covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. The VH and VL domains consist of four regions of relatively conserved sequences called framework regions (FR1, FR2, FR3, and FR4), which form a scaffold for three regions of hypervariable sequences (complementarity determining regions, CDRs). The CDRs contain most of the residues responsible for specific interactions of the antibody with the antigen. CDRs are referred to as CDR 1 , CDR2, and CDR3. Accordingly, CDR constituents on the heavy chain are referred to as H1, H2, and H3, while CDR constituents on the light chain are referred to as L1, L2, and L3. The term "variable" refers to the portions of the immunoglobulin domains that exhibit variability in their sequence and that are involved in determining the specificity and binding affinity of a particular antibody (i.e. the "variable domain(s)"). Variability is not evenly distributed throughout the variable domains of antibodies; it is concentrated in sub-domains of each of the heavy and light chain variable regions. These sub-domains are called "hypervariable" regions or "complementarity determining regions" (CDRs). The more conserved (i.e. non hypervariable) portions of the variable domains are called the "framework" regions (FRM). The variable domains of naturally occurring heavy and light chains each comprise four FRM regions, largely adopting a b- sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases forming part of, the b -sheet structure. The hypervariable regions in each chain are held together in close proximity by the FRM and, with the hypervariable regions from the other chain, contribute to the formation of the antigen- binding site. The constant domains are not directly involved in antigen binding, but exhibit various effector functions, such as, for example, antibody- dependent, cell-mediated cytotoxicity and complement activation. [0044] The terms "CDR", and its plural "CDRs", refer to a complementarity determining region (CDR) of which three make up the binding character of a light chain variable region (CDRL1, CDRL2 and CDRL3) and three make up the binding character of a heavy chain variable region (CDRH1, CDRH2 and CDRH3). CDRs contribute to the functional activity of an antibody molecule and are separated by amino acid sequences that comprise scaffolding or framework regions. The exact definitional CDR boundaries and lengths are subject to different classification and numbering systems. Despite differing boundaries, each of these systems has some degree of overlap in what constitutes the so called "hypervariable regions" within the variable sequences. CDR definitions according to these systems may therefore differ in length and boundary areas with respect to the adjacent framework region. See for example Kabat, Chothia, and/or MacCallum (Kabat et al., loc. cit. ; Chothia et al. , J Mol Biol (1987), 196: 901; and MacCallum et al., J Mol Biol (1996), 262: 732). However, the numbering in accordance with the so-called Kabat system is preferred.

[0045] The term "hypervariable region" (also known as "complementarity determining regions" or CDRs) as used herein refers to the amino acid residues of an antibody which are (usually three or four short regions of extreme sequence variability) within the V-region domain of an immunoglobulin which form the antigen-binding site and are the main determinants of antigen specificity. There are at least two methods for identifying the CDR residues: (1) An approach based on cross-species sequence variability (i.e. Kabat et a!., loc. cit.)] and (2) An approach based on crystallographic studies of antigen-antibody complexes (Chothia, C. et al., J Mol Biol (1987), 196: 901-917). However, to the extent that two residue identification techniques define regions of overlapping, but not identical regions, they can be combined to define a hybrid CDR. However, in general, the CDR residues are preferably identified in accordance with the so-called Kabat (numbering) system. The term "framework region" refers to the art-recognized portions of an antibody variable region that exist between the more divergent (i.e. hypervariable) CDRs. Such framework regions are typically referred to as frameworks 1 through 4 (FR1, FR2, FR3, and FR4) and provide a scaffold for the presentation of the six CDRs (three from the heavy chain and three from the light chain) in three dimensional space, to form an antigen-binding surface. The term "canonical structure" refers to the main chain conformation that is adopted by the antigen binding (CDR) loops. From comparative structural studies, it has been found that five of the six antigen binding loops have only a limited repertoire of available conformations. Each canonical structure can be characterized by the torsion angles of the polypeptide backbone. Correspondent loops between antibodies may, therefore, have very similar three dimensional structures, despite high amino acid sequence variability in most parts of the loops (Chothia and Lesk, J Mol Biol (1987), 196: 901; Chothia et al., Nature (1989), 342: 877; Martin and Thornton, J Mol Biol (1996), 263: 800, each of which is incorporated by reference in its entirety). Furthermore, there is a relationship between the adopted loop structure and the amino acid sequences surrounding it. The conformation of a particular canonical class is determined by the length of the loop and the amino acid residues residing at key positions within the loop, as well as within the conserved framework (i.e. outside of the loop). Assignment to a particular canonical class can therefore be made based on the presence of these key amino acid residues. The term "canonical structure" may also include considerations as to the linear sequence of the antibody, for example, as catalogued by Kabat (Kabat et al., loc. cit.). The Kabat numbering scheme (system) is a widely adopted standard for numbering the amino acid residues of an antibody variable domain in a consistent manner and is the preferred scheme applied in the present invention as also mentioned elsewhere herein. Additional structural considerations can also be used to determine the canonical structure of an antibody. For example, those differences not fully reflected by Kabat numbering can be described by the numbering system of Chothia et al and/or revealed by other techniques, for example, crystallography and two or three-dimensional computational modeling. Accordingly, a given antibody sequence may be placed into a canonical class which allows for, among other things, identifying appropriate chassis sequences (e.g., based on a desire to include a variety of canonical structures in a library).

[0046] CDR3 is typically the greatest source of molecular diversity within the antibody binding site. H3, for example, can be as short as two amino acid residues or greater than 26 amino acids. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known in the art. For a review of the antibody structure, see Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, eds. Harlow et al., 1988. One of skill in the art will recognize that each subunit structure, e.g., a CH, VH, CL, VL, CDR, FR structure, comprises active fragments, e.g., the portion of the VH, VL, or CDR subunit the binds to the antigen, i.e., the antigen-binding fragment, or, e.g., the portion of the CH subunit that binds to and/or activates, e.g., an Fc receptor and/or complement. The CDRs typically refer to the Kabat CDRs, as described in Sequences of Proteins of immunological Interest, US Department of Health and Human Services (1991), eds. Kabat et al. Another standard for characterizing the antigen binding site is to refer to the hypervariable loops as described by Chothia. See, e.g., Chothia et al., J Mol Biol (1992), 227:799-817; and Tomlinson et al., EMBO J (1995), 14: 4628-4638. Still another standard is the AbM definition used by Oxford Molecular's AbM antibody modelling software. See, generally, e.g., Protein Sequence and Structure Analysis of Antibody Variable Domains. In: Antibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg). The sequence of antibody genes after assembly and somatic mutation is highly varied, and these varied genes are estimated to encode 10 ¹⁰ different antibody molecules (Immunoglobulin Genes, 2nd ed., eds. Jonio et al., Academic Press, San Diego, CA, 1995). Accordingly, the immune system provides a repertoire of immunoglobulins. The term "repertoire" refers to at least one nucleotide sequence derived wholly or partially from at least one sequence encoding at least one immunoglobulin. The sequence(s) may be generated by rearrangement in vivo of the V, D, and J segments of heavy chains, and the V and J segments of light chains. Alternatively, the sequence(s) can be generated from a cell in response to which rearrangement occurs, e.g., in vitro stimulation. Alternatively, part or all of the sequence(s) may be obtained by DNA splicing, nucleotide synthesis, mutagenesis, and other methods, see, e.g., U.S. Patent 5,565,332. A repertoire may include only one sequence or may include a plurality of sequences, including ones in a genetically diverse collection.

[0047] As used herein, unless specified otherwise, the term "antibody" does not only refer to an immunoglobulin (or intact antibody), but also to a fragment thereof, and encompasses any polypeptide comprising an antigen-binding fragment or an antigen-binding domain. Preferably, the fragment such as Fab, F(ab') ₂ , Fv, scFv, Fd, dAb, and other antibody fragments that retain antigen-binding function. Typically, such fragments would comprise an antigen-binding domain and have the same properties as the antibodies described herein.

[0048] The term “antibody” as used herein includes antibodies that compete for binding to the same epitope as the epitope bound by the antibodies of the present invention, preferably obtainable by the methods for the generation of an antibody as described herein elsewhere. To determine if a test antibody can compete for binding to the same epitope, a cross blocking assay e.g., a competitive ELISA assay can be performed. In an exemplary competitive ELISA assay, epitope-coated wells of a microtiter plate, or epitope-coated sepharose beads, are pre-incubated with or without candidate competing antibody and then a biotin-labeled antibody of the invention is added. The amount of labeled antibody bound to the epitope in the wells or on the beads is measured using avidin-peroxidase conjugate and appropriate substrate. Alternatively, the antibody can be labeled, e.g., with a radioactive or fluorescent label or some other detectable and measurable label. The amount of labeled antibody that binds to the antigen will have an inverse correlation to the ability of the candidate competing antibody (test antibody) to compete for binding to the same epitope on the antigen, i.e. the greater the affinity of the test antibody for the same epitope, the less labeled antibody will be bound to the antigen-coated wells. A candidate competing antibody is considered an antibody that binds substantially to the same epitope or that competes for binding to the same epitope as an antibody of the invention if the candidate competing antibody can block binding of the antibody by at least 20%, preferably by at least 20-50%, even more preferably, by at least 50% as compared to a control performed in parallel in the absence of the candidate competing antibody (but may be in the presence of a known noncompeting antibody). It will be understood that variations of this assay can be performed to arrive at the same quantitative value.

[0049] The term “antibody” also includes but is not limited to polyclonal, monoclonal, monospecific, polyspecific such as bispecific, non-specific, humanized, human, single-chain, chimeric, synthetic, recombinant, hybrid, mutated, grafted, and in vitro generated antibodies. In one embodiment of the present invention, the antibody binding to an HERV Env protein or to its respective receptor is a monoclonal antibody (mAb; MAb). In context with the present invention, commercially available antibodies that may be employed in accordance with the present invention comprise those listed in Table II herein.

Table II: Antibodies against HERV

[0050] Accordingly, the term "antibody" also relates to a purified serum, i.e. a purified polyclonal serum. Accordingly, said term preferably relates to a serum, more preferably a polyclonal serum and most preferably to a purified (monoclonal or polyclonal) serum. The antibody/serum is obtainable, and preferably obtained, for example, by the method or use described herein. "Polyclonal antibodies" or "polyclonal antisera" refer to immune serum containing a mixture of antibodies specific for one (monovalent or specific antisera) or more (polyvalent antisera) antigens which may be prepared from the blood of animals immunized with the antigen or antigens. A non-limiting example of such an antibody beyond the examples given in table II may be an antibody which is capable of binding to the amino acid sequence shown in SEQ ID NOs: 22 - 23 or to a portion thereof.

[0051] Furthermore, the term "antibody" as employed in the invention also relates to derivatives or variants of the antibodies described herein which display the same specificity as the described antibodies. Examples of "antibody variants" include humanized variants of non- human antibodies, "affinity matured" antibodies (see, e.g., Hawkins et al., J Mol Biol (1992), 254, 889-896; and Lowman et al., Biochemistry (1991), 30: 10832- 10837) and antibody mutants with altered effector function (s) (see, e.g., US Patent 5, 648, 260). The terms "antigen-binding domain", "antigen-binding fragment" and “antibody binding region” when used herein refer to a part of an antibody molecule that comprises amino acids responsible for the specific binding between antibody and antigen. The part of the antigen that is specifically recognized and bound by the antibody is referred to as the "epitope" as described herein above. As mentioned above, an antigen-binding domain may typically comprise an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH); however, it does not have to comprise both. Fd fragments, for example, have two VH regions and often retain some antigen-binding function of the intact antigen-binding domain. Examples of antigen-binding fragments of an antibody include (1) a Fab fragment, a monovalent fragment having the VL, VH, CL and CH1 domains; (2) a F(ab')2 fragment, a bivalent fragment having two Fab fragments linked by a disulfide bridge at the hinge region; (3) a Fd fragment having the two VH and CH1 domains; (4) a Fv fragment having the VL and VH domains of a single arm of an antibody, (5) a dAb fragment (Ward et al., (1989) Nature 341 :544-546), which has a VH domain; (6) an isolated complementarity determining region (CDR), and (7) a single chain Fv (scFv). Although the two domains of the Fv fragment, VL and VH> are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al., (1988) Science (1988), 242: 423-426; and Huston et al., (1988) PNAS USA (1988), 85: 5879-5883). These antibody fragments are obtained using conventional techniques known to those with skill in the art, and the fragments are evaluated for function in the same manner as are intact antibodies.

[0052] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e. the individual antibodies comprising the population are identical except for possible naturally occurring mutations and/or post- translation modifications (e.g., isomerizations, amidations) that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to conventional (polyclonal) antibody preparations which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they are synthesized by the hybridoma culture, uncontaminated by other immunoglobulins. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al., Nature (1975), 256: 495, or may be made by recombinant DNA methods (see, e.g., U. S. Patent No. 4,816, 567). The "monoclonal antibodies" may also be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature (1991), 352: 624- 628; and Marks et al., J Mol Biol (1991), 222: 581-597, for example. The monoclonal antibodies herein specifically include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain (s) is (are) identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U. S. Patent No. 4,816, 567; Morrison et al., PNAS USA (1984), 81: 6851-6855). Chimeric antibodies of interest herein include "primitized" antibodies comprising variable domain antigen-binding sequences derived from a non-human primate (e.g., Old World Monkey, Ape etc.) and human constant region sequences. "Humanized" forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F (ab ¹ ) 2 or other antigen-binding subsequences of antibodies) of mostly human sequences, which contain minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region (also CDR) of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity, and capacity. In some instances, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, "humanized antibodies" as used herein may also comprise residues which are found neither in the recipient antibody nor the donor antibody. These modifications are made to further refine and optimize antibody performance. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al. , Nature (1986), 321: 522-525; Reichmann et al., Nature (1988), 332: 323-329; and Presta, Curr. Op. Struct Biol (1992), 2: 593-596.

[0053] The term "human antibody" includes antibodies having variable and constant regions corresponding substantially to human germline immunoglobulin sequences known in the art, including, for example, those described by Kabat et al. (See Kabat et al., loc. cit.). The human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs, and in particular, CDR3. The human antibody can have at least one, two, three, four, five, or more positions replaced with an amino acid residue that is not encoded by the human germline immunoglobulin sequence. As used herein, "in vitro generated antibody" refers to an antibody where all or part of the variable region (e.g., at least one CDR) is generated in a non-immune cell selection (e.g., an in vitro phage display, protein chip or any other method in which candidate sequences can be tested for their ability to bind to an antigen). This term thus preferably excludes sequences generated by genomic rearrangement in an immune cell. A "bispecific" or "bifunctional antibody" is an artificial hybrid antibody having two different heavy/light chain pairs and two different binding sites. Bispecific antibodies can be produced by a variety of methods including fusion of hybridomas or linking of Fab' fragments. See, e.g., Songsivilai & Lachmann, Clin Exp Immunol (1990), 79: 315-321; Kostelny et al., J Immunol (1992), 148: 1547-1553. In one embodiment, the bispecific antibody comprises a first binding domain polypeptide, such as a Fab' fragment, linked via an immunoglobulin constant region to a second binding domain polypeptide.

[0054] Numerous methods known to those skilled in the art are available for obtaining antibodies or antigen-binding fragments thereof. For example, antibodies can be produced using recombinant DNA methods (U.S. Patent 4,816,567). Monoclonal antibodies may also be produced by generation of hybridomas (see e.g., Kohler and Milstein, Nature (1975), 256: 495-499) in accordance with known methods. Hybridomas formed in this manner are then screened using standard methods, such as enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (BIACORE™) analysis, to identify one or more hybridomas that produce an antibody that specifically binds with a specified antigen. Any form of the specified antigen may be used as the immunogen, e.g., recombinant antigen, naturally occurring forms, any variants or fragments thereof, as well as antigenic peptide thereof. One exemplary method of making antibodies includes screening protein expression libraries, e.g., phage or ribosome display libraries. Phage display is described, for example, in U.S. Patent No. 5,223,409; Smith, Science (1985), 228: 1315-1317; Clackson et ai., Nature (1991), 352: 624-628; Marks et a/., J Mol Biol (1991), 222: 581-597WO 92/18619; WO 91/17271; WO 92/20791; WO 92/15679; WO 93/01288; WO 92/01047; WO 92/09690; and WO 90/02809. In another embodiment, a monoclonal antibody may be obtained from the non-human animal, and then modified, e.g., humanized, deimmunized, chimeric, may be produced using recombinant DNA techniques known in the art. A variety of approaches for making chimeric antibodies have been described. See, e.g., Morrison et ai, PNAS USA (1985), 81: 6851; Takeda et al., Nature (1985), 314: 452; U.S. Patent No. 4,816,567; U.S. Patent No. 4,816,397; EP 171496; EP 173494, GB 2177096. Humanized antibodies may also be produced, for example, using transgenic mice that express human heavy and light chain genes, but are incapable of expressing the endogenous mouse immunoglobulin heavy and light chain genes. Winter describes an exemplary CDR-grafting method that may be used to prepare the humanized antibodies described herein (U.S. Patent No. 5,225,539). All of the CDRs of a particular human antibody may be replaced with at least a portion of a non-human CDR, or only some of the CDRs may be replaced with non-human CDRs. It is only necessary to replace the number of CDRs required for binding of the humanized antibody to a predetermined antigen. Humanized antibodies or fragments thereof can be generated by replacing sequences of the Fv variable domain that are not directly involved in antigen binding with equivalent sequences from human Fv variable domains. Exemplary methods for generating humanized antibodies or fragments thereof are provided by Morrison, Science (1985), 229: 1202-1207; Oi et al., BioTechniques (1986), 4: 214; US 5,585,089; US 5,693,761; US 5,693,762; US 5,859,205; and US 6,407,213. Those methods include isolating, manipulating, and expressing the nucleic acid sequences that encode all or part of immunoglobulin Fv variable domains from at least one of a heavy or light chain. Such nucleic acids may be obtained from a hybridoma producing an antibody against a predetermined target, as described above, as well as from other sources. The recombinant DNA encoding the humanized antibody molecule can then be cloned into an appropriate expression vector. In certain embodiments, humanized antibody may be optimized by the introduction of conservative substitutions, consensus sequence substitutions, germline substitutions and/or backmutations. Such altered immunoglobulin molecules can be made by any of several techniques known in the art, (e.g., Teng et al., PNAS USA (1983), 80: 7308-731; Kozbor et al., Immunology Today (1983), 4: 7279; Olsson et al., Meth Enzymol (1982), 92: 3-16), and may be made according to the teachings of WO 92/06193 or EP 239400).

[0055] Examples of anti-HERV Env protein-antibodies may bind to the amino acid sequence of the HERV Env protein. Illustrative and non-limiting examples of such amino acid sequences are shown in SEQ ID NO: 101 to 139. Thus, an anti-HERV Env protein-antibody capable of binding to the amino acid sequence of HERV K shown in SEQ ID NOs: 101 to 128 or to a portion thereof may be used in treating Tauopathy, or Parkinson’s disease is envisaged herein. Further, an anti-HERV Env protein-antibody capable of binding to the amino acid sequence of HERV W shown in SEQ ID NOs: 129 to 131 or to a portion thereof may be used treating Tauopathy, or Parkinson’s disease is encompassed. Likewise an anti- HERV Env protein-antibody capable of binding to the amino acid sequence of HERV H shown in SEQ ID NOs: 132 to 137 or to a portion thereof may be used in treating Tauopathy, or Parkinson’s disease is an illustrative example. Finally, an anti-HERV Env protein-antibody capable of binding to the amino acid sequence of HERV R shown in SEQ ID NOs: 138 to 139 or to a portion thereof may be used in treating Tauopathy, or Parkinson’s disease is also envisaged herein.

[0056] In a similar manner HERV Gag amino acid sequences may be targeted by antibodies and these antibodies thus may fulfill the task of an inhibitor as mentioned herein. Therefore, an anti-HERV Env protein-antibody capable of binding to the amino acid sequence of HERV Gag shown in SEQ ID NOs: 22 to 23 or to a portion thereof may be used in treating Tauopathy, or Parkinson’s disease.

[0057] As has further been found in context with the present invention, HERV Env proteins as described and defined herein can be used as biomarkers for diagnosing a tauopathy (e.g., Alzheimer’s Disease (AD), Argyrophilic Grain Disease (AGD), Cortical Basal Degeneration (CBD), Progressive Supranuclear Palsy (PSP), Pick’s Disease (PiD), and Frontotemporal Dementia with Parkinsonism related to chromosome 17 (FTDP-17)), Parkinson’s disease and ALS. Particularly, as found in context with the present invention, HERV Env proteins are upregulated and overexpressed in different tauopathies. For example, as has been found in context with the present invention, HERV-W is upregulated in AD patients, while HERV-FRD, H and R(b) are associated with CBD disease, and HERV-K and F(c)1 are increased in PSP patients. Accordingly, in accordance with the present invention, molecules binding to HERV Env proteins or (a) fragment(s) or to nucleic acid molecules encoding such HERV Env proteins or (a) fragment(s) thereof may be used for diagnosing tauopathy (e.g., Alzheimer’s Disease (AD), Argyrophilic Grain Disease (AGD), Cortical Basal Degeneration (CBD), Progressive Supranuclear Palsy (PSP), Pick’s Disease (PiD), and Frontotemporal Dementia with Parkinsonism related to chromosome 17 (FTDP-17), Parkinson’s disease and ALS. In specific embodiments of the present invention, molecules binding to specific HERV-Env proteins or (a) fragment(s) which are associated with specific tauopathies or with nucleic acid molecules encoding such specific HERV Env proteins or (a) fragment(s) thereof may be used for diagnosing corresponding specific tauopathies. For example, in this context, such specific

BO tauopathy-HERV Env protein association has been shown in context with the present invention for (1) HERV-W and AD, (2) HERV-FRD & HERV-H & HERV-R(b) and CBD, and (3) HERV-K & HERV-F(c)1 and PSP.

[0058] Accordingly, the present invention also relates to molecules binding to HERV Env protein or a fragment thereof, or to a nucleic acid molecule encoding said HERV Env protein or a fragment thereof, for use in diagnosing a tauopathy (e.g., Alzheimer’s Disease (AD), Argyrophilic Grain Disease (AGD), Cortical Basal Degeneration (CBD), Progressive Supranuclear Palsy (PSP), Pick’s Disease (PiD), and Frontotemporal Dementia with Parkinsonism related to chromosome 17 (FTDP-17)), Parkinson’s disease, or ALS. In one embodiment of the present invention, such molecule binding to HERV Env protein or a fragment thereof may be any binding agent as described and defined herein in context with inhibitors of HERV Env proteins. Preferably, such binding agent is suitable to be employed in a protein detection system, for example - but not limited to - ELISA, ELIA, Western blot, IHC, and other protein detection systems known in the art. In one embodiment, such HERV Env protein binding agent is an antibody as described and defined herein. In a further embodiment, such binding agents may be labelled (depending on the assay used as readily clear for the skilled person).

[0059] In another embodiment of the present invention, such molecule binding to a nucleic acid molecule encoding a HERV Env protein or a fragment thereof may be any nucleic acid molecule as described and defined herein in context with inhibitors of HERV Env protein expression (e.g., transcription or translation) which is suitable for specifically detecting a nucleic acid molecule. Preferably, it is a nucleotide probe, hybridizing (preferably under stringent conditions) or being complementary to at least a portion of a nucleic acid molecule encoding a HERV Env protein or a fragment thereof. For example, such nucleic acid molecules may be selected from the group consisting of decoy nucleic acid molecules, primers, or other probe molecules suitable in corresponding assays for specific DNA or RNA sequence identification. Such assays include inter alia PCR (incl. RT, real-time, quantitative), Southern/ Northern blot, microarray, etc. In one embodiment, such probe molecules for specific DNA or RNA sequence identification may be labelled (depending on the assay used as readily clear for the skilled person).

[0060] In context with the present invention, the tauopathy to be treated or diagnosed as described herein is to be understood as known in the art and may comprise any disease or disorder associated with generation, aggregation, or overexpression of Tau protein. In accordance with the present invention, examples of tauopathies comprise Alzheimer’s Disease (AD), Argyrophilic Grain Disease (AGD), Cortical Basal Degeneration (CBD), Progressive Supranuclear Palsy (PSP), Pick’s Disease (PiD), and Frontotemporal Dementia with Parkinsonism related to chromosome 17 (FTDP-17), particularly AD, AGD, CBD and PSP, more particularly AD, CBD and PSP.

[0061] The inventors were able to demonstrate that an shRNA directed against HERV Env (here: HERV-W Syncytin-1) can reduce intercellular Tau aggregate spreading (breast cancer cell line MCF-7, Figure 14), that the (HIV) protease inhibitor Lopinavir reduces intercellular Tau aggregate spreading (melanoma cells expressing HERV (Figure 15), and that the receptor interactions between HERV Env (HERV-W Syncytin-1) and its receptors (here: ASCT1 and ASCT2; genes SLC1A4/ SLC1A5) enhances intercellular protein aggregate spreading (HEK cells, Figure 16).

[0062] Thus, it is encompassed to use a nucleotide sequence against HERV Env proteins (e.g. HERV-W Syncytin-1 or HERV-W Syncytin-2), or the (HIV) protease inhibitor Lopinavir, to reduce Tau aggregate spreading. A nucleotide sequence directed against the nucleotide sequence of HERV Env shown in any one of SEQ ID NOs: 1 to 13, for use in treating Tauopathy, or Parkinson’s disease is encompassed by the present invention. An illustrative example of such a nucleotide sequence may be the sequence shown in SEQ ID NOs: 42 to 72, or SEQ ID NO: 98 or the murine sequences shown in SEQ ID NOs: 25 to 29. Further, a nucleotide sequence directed against HERV-W Syncytin-1 for use in treating Tauopathy, or Parkinson’s disease as well as a nucleotide sequence directed against HERV-W Syncytin-2 for use in treating Tauopathy, or Parkinson’s disease are embodiments of the present invention.

[0063] Likewise, a nucleotide sequence directed against the nucleotide sequence of HERV Gag shown in any one of SEQ ID NOs: 14 to 21 or encoded by a nucleotide sequence that has at least about 85% sequence identity to any one of SEQ ID NOs: 14 to 21, for use in treating Tauopathy, or Parkinson’s disease, is envisaged herein. A nucleic acid molecule hybridizing to at least a portion of the nucleotide sequence of HERV Gag shown in any one of SEQ ID NOs: 14 to 21 for use in treating Tauopathy, or Parkinson’s disease, is directed to bind anywhere in the respective DNA sequence. Further, a nucleic acid molecule comprising any one of the nucleotide sequence shown in any one of SEQ ID NOs: 30 to 35 for use in treating Tauopathy, or Parkinson’s disease, depicts different nucleotide sequence variants, capable of binding selectively to the respective Gag proteins. It is further envisaged that the interaction between HERV Env and its respective receptors ASCT1 (gene SLC1A4 ), ASCT2 (gene SLC1A4), (and the complex of CD98HC and LAT 1 which may functions as HERV Env receptor) are blocked, to reduce aggregate spreading. Thus, an inhibitor of a HERV Env protein capable of blocking the binding of HERV Env to its receptor ASCT1 (gene SLC1A4), ASCT2 (gene SLC1A5) for use in treating Tauopathy, Parkinson’s disease, is encompassed herein. Said inhibitor may be a nucleic acid hybridizing to at least a portion of the nucleotide sequence of SLC1A4 (SEQ ID NO: 99) or SLCA4 (SEQ ID NO: 100). Thus, a nucleic acid molecule capable of blocking the HERV Env receptor ASCT1 (gene SLC1A4) or ASCT2 (gene SLC1 A5) by hybridizing to at least a portion of the nucleotide sequence shown in SEQ ID NO: 99 or SEQ ID NO: 100 for use in treating Tauopathy, Parkinson’s disease.

[0064] The present invention may also be characterized by the following items:

Item 1. Inhibitor of a HERV Env protein, proteins comprising HERV Env, or a fragment thereof, for use in treating Tauopathy, Parkinson’s disease, or ALS.

Item 2. Inhibitor of item 1, wherein said inhibitor inhibits maturation or expression of said HERV Env protein, and/or binding of said HERV Env protein to a receptor.

Item 3. Inhibitor of item 1 or 2, wherein said inhibitor inhibits maturation of said HERV Env protein, and wherein said inhibitor is a HERV protease inhibitor.

Item 4. Inhibitor of item 1 or 2, wherein said inhibitor inhibits expression of said HERV Env protein, and wherein said inhibitor is a nucleic acid molecule hybridizing to at least a portion of the nucleic acid sequence encoding said HERV Env protein.

Item 5. Inhibitor of item 1 or 2, wherein said inhibitor inhibits binding of said HERV Env protein to a receptor.

Item 6. Inhibitor of item 5, which is an anti-HERV Env protein-antibody.

Item 7. Inhibitor of a receptor binding a HERV Env protein for use in treating Tauopathy, Parkinson’s disease, or ALS.

Item 8. Inhibitor of item 7, wherein said inhibitor inhibits maturation or expression of said receptor, and/or binding of HERV Env protein to said receptor.

Item 9. Inhibitor of item 7 or 8, which is a nucleic acid molecule complementary to at least a portion of the nucleic acid sequence encoding said receptor. Item 10. Inhibitor of item 7 or 8, which is an antibody binding to said receptor or a fragment thereof.

Item 11. Inhibitor of any one of items 7 to 10, wherein said receptor is selected from the group consisting of ASCT1 and ASCT2 (genes SLC1A4/ SLC1A5).

Item 12. Molecule binding to HERV Env protein or a fragment thereof, or to a nucleic acid molecule encoding said HERV Env protein or a fragment thereof, for use in diagnosing a Tauopathy, Parkinson’s disease, or ALS.

Item 13. Molecule of item 12, which is an anti-HERV Env protein-antibody.

Item 14. Molecule of item 12, which is a nucleic acid molecule binding to the nucleic acid molecule encoding HERV Env protein or a fragment thereof.

Item 15. Inhibitor of any one of items 1 to 11 or molecule of any one of items 12 to 14, wherein said Tauopathy is selected from the group consisting of Alzheimer’s Disease (AD), Argyrophilic Grain Disease (AGD), Cortical Basal Degeneration (CBD), Progressive Supranuclear Palsy (PSP), Pick’s Disease (PiD), and Frontotemporal Dementia with Parkinsonism related to chromosome 17 (FTDP-17).

Item 16. The inhibitor of any one of the preceding items, wherein the inhibitor is any one of a HERV protease inhibitor, a nucleic acid binding to the nucleic acid molecule encoding a HERV Env protein, or an anti-HERV Env protein-antibody.

Item 17. A HERV protease inhibitor for use in treating Tauopathy, or Parkinson’s disease.

Item 18. The HERV protease inhibitor of item 17, wherein the protease inhibitor is any one of amprenavir, lopinavir, darunavir, indinavir, atazanavir, fosamprenavir, nelfinavir, ritonavir, saquinavir, tipranavir, amprenavir or atazanavir.

Item 19. The HERV protease inhibitor of any one of items 17 or 18, wherein the protease inhibitor is preferably amprenavir, atazanavir, or lopinavir.

Item 20. The inhibitor of any one of the preceding items, wherein the HERV Env protein is encoded by the nucleotide sequence shown in any one of SEQ ID NOs: 1 to 13 or encoded by a nucleotide sequence that has at least about 85% sequence identity to any one of SEQ ID NOs: 1 to 13.

Item 21. A nucleic acid molecule hybridizing to at least a portion of the nucleotide sequence encoding the HERV Env protein shown in any one of SEQ ID NOs: 1 to 13 or encoded by a nucleotide sequence that has at least about 85% sequence identity to any one of SEQ ID NOs: 1 to 13for use in treating Tauopathy, or Parkinson’s disease.

Item 22. A nucleic acid molecule comprising any one of the nucleotide sequence shown in any one of SEQ ID NOs: 42 to 72 for use in treating Tauopathy, or Parkinson’s disease.

Item 23. An anti-HERV Env protein-antibody capable of binding to the amino acid sequence of HERV K shown in SEQ ID NOs: 101 to 128 or to a portion thereof for use in treating Tauopathy, or Parkinson’s disease.

Item 24. An anti-HERV Env protein-antibody capable of binding to the amino acid sequence of HERV W shown in SEQ ID NOs: 129 to 131 or to a portion thereof for use in treating Tauopathy, or Parkinson’s disease.

Item 25. An anti-HERV Env protein-antibody capable of binding to the amino acid sequence of HERV H shown in SEQ ID NOs: 132 to 137 or to a portion thereof for use in treating Tauopathy, or Parkinson’s disease.

Item 26. An anti-HERV Env protein-antibody capable of binding to the amino acid sequence of HERV R shown in SEQ ID NOs: 138 to 139 or to a portion thereof for use in treating Tauopathy, or Parkinson’s disease.

Item 27. The inhibitor of any one of the preceding items, wherein the HERV Gag protein is encoded by the nucleotide sequence shown in any one of SEQ ID NOs: 14 to 21 or encoded by a nucleotide sequence that has at least about 85% sequence identity to any one of SEQ ID NOs: 14 to 21.

Item 28. A nucleic acid molecule hybridizing to at least a portion of the nucleotide sequence of HERV Gag shown in any one of SEQ ID NOs: 14 to 21 or encoded by a nucleotide sequence that has at least about 85% sequence identity to any one of SEQ ID NOs: 14 to 21 for use in treating Tauopathy, or Parkinson’s disease.

Item 29. A nucleic acid molecule comprising any one of the nucleotide sequence shown in any one of SEQ ID NOs: 30 to 35 for use in treating Tauopathy, or Parkinson’s disease.

Item 30. An anti-HERV Env protein-antibody capable of binding to the amino acid sequence of HERV Gag shown in SEQ ID NOs: 22 to 23 or to a portion thereof for use in treating Tauopathy, or Parkinson’s disease.

Item 31. A nucleic acid molecule capable of blocking the HERV Env receptor ASCT1 (gene SLC1A4) or ASCT2 (gene SLC1A5) by hybridizing to at least a portion of the nucleotide sequence shown in SEQ ID NO: 99 or SEQ ID NO: 100 for use in treating Tauopathy, Parkinson’s disease.

Item 32. The inhibitor of item 16, wherein the inhibitor comprises the HERV protease inhibitor of any one of item 17 to 19, the nucleic acid of any one of item 22 to 23 or item 28 to 29, or item 31 , or the anti-HERV Env protein-antibody of any one of item 23 to 26 or item 30.

[0065] The embodiments which characterize the present invention are described herein, shown in the Figures, illustrated in the Examples, and reflected in the claims.

[0066] It must be noted that as used herein, the singular forms “a”, “an”, and “the”, include plural references unless the context clearly indicates otherwise. Thus, for example, reference to “a reagent” includes one or more of such different reagents and reference to “the method” includes reference to equivalent steps and methods known to those of ordinary skill in the art that could be modified or substituted for the methods described herein.

[0067] Unless otherwise indicated, the term "at least" preceding a series of elements is to be understood to refer to every element in the series. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention. [0068] The term "and/or" wherever used herein includes the meaning of "and", "or" and "all or any other combination of the elements connected by said term".

[0069] The term "about" or "approximately" as used herein means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

[0070] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. When used herein the term “comprising” can be substituted with the term “containing” or “including” or sometimes when used herein with the term “having”.

[0071] When used herein “consisting of" excludes any element, step, or ingredient not specified in the claim element. When used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim.

[0072] In each instance herein any of the terms "comprising", "consisting essentially of" and "consisting of may be replaced with either of the other two terms.

[0073] It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention, which is defined solely by the claims.

[0074] All publications and patents cited throughout the text of this specification (including all patents, patent applications, scientific publications, manufacturer’s specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. To the extent the material incorporated by reference contradicts or is inconsistent with this specification, the specification will supersede any such material.

[0075] Sequences referred to herein comprise:

SEQ ID NO: 1 H. sapiens DNA >HERV-H Env consensus sequence (AJ289711, AJ289710, AJ289709)

AT GACAGAGAAATTCCTTTTCCTTT AT CTTTCCCTCCTTCCCATGCCCCT ACT CT CAC AG GCAC AGT GG AAT G AAAATTCCCTT GT CAGTTTTTCCAAAAT AATT GCTTCGGG AAACCAT CTAAGCAACTGTTGGATCTGCCACAACTTCATCACCAGGTCCTCATCTTACCAATATATT TTGGT AAGAAATTTTTCTTT AAACCT AACATTTGGTTCAGGAATCCCT GAAGGCCAACAT AAATCTGTTCCGCTCCAGGTTTCGCTTGCTAACTCAGCGCACCAAGTCCCCTGCCTGGA T CT CACTCCACCTTT CAAT CAAAGCT CT AAAACTTCTTT CT ATTT CT ACAACTGCT CTT CT CT AAACCAAACCT GTT GTCCATGCCCT GAAGGACACT GT GACAGGAAGAACACCTCT GA GGAGGGATTCCCCAGTCCCACCATCCATCCCATGAGCTTCTCCCCAGCAGGCTGCCAC CCT AACTT GACT CACTGGTGTCCAGCT AAACAAAT G AACG ATT ATCG AG ACAAGT CACC CCAAAACCGCT GTGCAGCTTGGGAAGGAAAAGAGCT AATCACATGGAGGGTTCT AT ATT CGCTTCCCAAGGCACACACTGTCCCCACATGGCCAAAATCTACTGTTCCCCTGGGAGG GCCTCTATCCCCTGCATGCAATCAAACTATTCCAGCAGGGTGGAAATCGCAGTTACACA AGTGGTTCGACAGCCACATCCCCCGGTGGGCCTGTACCCCTCCTGGCTATGTATTTTTA TGT GGGCCACAAAAAAAT AAACT GCCCTTT GATGGAAGTCCT AAGAT AACCT ATT CAACC CCCCCTGTGGCAAACCTCTACACTTGCATTAATAACATCCAACATACGGGAGAATGTGC TGTGGGACTTTTGGGACCACGGGGGATAGGTGTGACCATTTATAACACCACCCAACCCA GACAGAAAAGAGCTCTGGGTCT AAT ACTGGCAGGGATGGGTGCGGCCAT AGGAAT GAT CGCCCC ATGGGG AGGGTT CACTT AT CAT GAT GT CACCCT CAGAAAT CT CTCCAGACAAA T AGACAACAT AGCT AAG AGT ACCAG AG AT AGCATCTCT AAACTCAAGGCCTCCAT AG ATT CT CT AGC AAAT GT AGTCAT GG ACAACAGATT GGCCTT AG ATT ACCT CTT AGCAG AGCAG GGTGGAGTCT GT GCAGT GATCAAT AAATCCT GTTGCGTTT AT GTCAAT AACAGT GGGGC GAT AGAGGAGGAT AT AAAAAAGAT CT AT GAT GAGGCT ACGTGGCTCCAT GACTTTGGAA AAGGAGGTGCTTCAGCAAGGGCCATCTGGGAGGCTGTGAAGTCTGCCCTCCCCTCCCT CAACTGGTTT GTCCCTTT ACTGGGACCAGCAACAGTT AT ACTCTT ACTTTTCCTCTTT GG CCCTT GTTT CTTT AATTT ACT GATT AAGT GTGTCT CTT CT AGG AT AAAGCAATTT CACAT G AAGTCCCCCCAAATGGAAAGATATCAGCTATCTGTCATTGGAGGCCCCAGCACCTATAA GCACATCTCCCCCTT GGAT GCCAGTGGGCAAAGATTCCGGGAAACT AT GGAGGAATTTT CTCTCTGA

SEQ ID NO: 2 H. sapiens DNA

>HERV K Env consensus sequence from 11 genes (Lee et al., PLoS Pathogens(2007),3(1):e10)

ATGAACCCATCGGAGATGCAAAGAAAAGCACCTCCGCGGAGACGGAGACACCGCAAT C G AGCACCGTT GACT CACAAG AT G AACAAAATGGT GACGTCAG AAG AACAGAT GAAGTT G CCATCCACCAAGAAGGCAGAGCCGCCGACTTGGGCACAACTAAAGAAGCTGACGCAGT TAGCT ACAAAAT AT CT AGAG AACACAAAGGT GACACAAACCCCAGAG AGT ATGCTGCTT GCAGCCTTGATGATTGTATCAATGGTGGTAAGTCTCCCTATGCCTGCAGGAGCAGCTGC AGCT AACT AT ACCT ACT GGGCCT AT GTGCCTTTCCCGCCCTT AATTCGGGCAGTCACAT GGATGGAT AATCCT AT AGAAGT AT AT GTT AAT GAT AGT GT AT GGGT ACCTGGCCCCAT AG AT GATCGCT GCCCT GCCAAACCT GAGGAAGAAGGGAT GAT GAT AAAT ATTTCCATTGGG T ATCGTT ATCCTCCT ATTTGCCT AGGGAGAGCACCAGGAT GTTT AATGCCTGCAGTCCA AAATTGGTTGGTAGAAGTACCTACTGTCAGTCCCATCAGTAGATTCACTTATCACATGGT AAGCGGG AT GTCACTCAGGCCACGGGT AAATT ATTT ACAAG ACTTTTCTT AT CAAAG AT C ATTAAAATTTAGACCTAAAGGGAAACCTTGCCCCAAGGAAATTCCCAAAGAATCAAAAAA T ACAG AAGTTTT AGTTT GGG AAG AAT GT GTGGCC AAT AGTGCGGT GAT ATT ACAAAACAA T GAATTTGGAACT ATT AT AGATT GGGCACCTCGAGGTCAATTCT ACCACAATTGCTCAGG ACAAACT CAGTCGT GTCCAAGT GCACAAGT GAGTCCAGCT GTT GAT AGCG ACTT AAC AG AAAGTTT AG ACAAACAT AAGCAT AAAAAATT GCAGTCTTT CT ACCCTTGGG AATGGGG AG AAAAAGGAAT CTCT ACCCC AAGACCAAAAAT AGT AAGTCCT GTTT CTGGTCCT GAACAT C CAGAATT ATGGAGGCTT ACT GT GGCCTCACACCACATT AGAATTTGGTCTGGAAATCAAA CTTT AG AAACAAGAG ATCGT AAGCCATTTT AT ACT GTCGACCT AAATTCCAGT CT AACAG TTCCTTT ACAAAGTTGCGT AAAGCCCCCTT AT ATGCT AGTT GT AGGAAAT AT AGTT ATT AA ACCAG ACTCCCAGACT ATAACCTGT GAAAATT GT AGATTGCTT ACTT GCATT GATT CAAC TTTTAATTGGCAACACCGTATTCTGCTGGTGAGAGCAAGAGAGGGCGTGTGGATCCCTG T GTCCATGG ACCG ACCGT GGG AGGCCT CACCATCCGTCCAT ATTTT G ACT G AAGT ATT A AAAGGT GTTTT AAAT AG ATCC AAAAG ATT CATTTTT ACTTT AATT GC AGT GATT AT GGG AT T AATTGCAGTCACAGCT ACGGCTGCT GT AGCAGGAGTTGCATT GCACTCTTCT GTTCAG T CAGT AAACTTT GTT AAT GATTGGCAA AAA AATT CT ACAAG ATT GT GG AATT CACAAT CT A GT ATT GAT CAAAAATT GGCAAAT CAAATT AAT GAT CTT AG ACAAACT GT C ATTT GG ATGG G AG AC AG ACTCAT G AGCTT AGAACATCGTTTCCAGTT ACAAT GT G ACTGG AAT ACGTCA GATTTTT GT ATT ACACCCCAAATTT AT AAT GAGTCT GAGCATCACTGGGACAT GGTT AGA CGCCAT CT ACAGGG AAG AGAAG AT AAT CT CACTTT AG ACATTTCC AAATT AAAAGAACAA ATTTTCGAAGCATCAAAAGCCCATTT AAATTTGGTGCCAGGAACT GAGGCAATTGCAGG AGTT GCT GATGGCCTCGCAAATCTT AACCCT GTCACTTGGGTT AAGACCATTGGAAGT A CT ACG ATT AT AAATCTCAT ATT AATCCTT GTGTGCCT GTTTT GTCTGTTGTT AGTCTGCAG GT GT ACCCAACAGCTCCGAAGAGACAGCGACCATCGAGAACGGGCCAT GAT GACGAT G GCGGTTTTGTCGAAAAGAAAAGGGGGAAATGTGGGGAAAAGCAAGAGAGATCAGATTG TTACTGTGTCTGTGT AG

SEQ ID NO: 3 H. sapiens DNA

>HERV T Env (AC078899)

ATGGGTCCCGAAGCCTGGGTCAGGCCCCTTAAAACTGCGCCTAAGCCGGGTGAAGCC A TT AGATT AATT CTTTTT ATTT ACCT CT CTT GTTT CTTTTTGCCT GTTATGTCCTCT G AGCCT TCCTACTCCTTTCTCCTCACCTCTTTCACAACAGGACGTGTATTCGCAAACACTACTTGG AGGGCCGGT ACCTCCAAGGAAGTCTCCTTTGCAGTT GATTT AT GT GT ACT GTTCCCAGA GCCAGCTCGTACCCATGAAGAGCAACATAATTTGCCGGTCATAGGAGCAGGAAGTGTC GACCTTGCAGCAGGATTTGGACACTCTGGGAGCCAAACTGGAT GTGGAAGCTCCAAAG GT GC AG AAAAAGGGCTCCAAAAT GTT G ACTTTT ACCT CT GTCCT GG AAAT CACCCT G AC GCT AGCT GT AGAGAT ACTT ACCAGTTTTTCTGCCCT GATTGGACAT GT GT AACTTT AGCC ACCTACTCTGGGGGATCAACTAGATCTTCAACTCTTTCCATAAGTCGTGTTCCTCATCCT AAATT ATGTACT AG AAAAAATT GT AATCCT CTT ACT AT AACT GTCCAT G ACCCT AATGCAG CTCAATGGT ATT ATGGCAT GTCATGGGGATT AAGACTTT AT ATCCCAGGATTT GAT GTT G GGACTATGTTCACCATCCAAAAGAAAATCTTGGTCTCATGGAGCTCCCCCAAGCCAATC GGGCCTTT AACT GAT CTAGGT GACCCT AT ATTCCAGAAACACCCT GACAAAGTT GATTT A ACTGTTCCTCTGCCATTCTTAGTTCCTAGACCCCAGCTACAACAACAACATCTTCAACCC AGCCT AAT GT CT AT ACT AGGT GG AGT ACACCAT CTCCTT AACCT CACCCAGCCT AAACT A GCCCAAGATT GTTGGCT AT GTTT AAAAGCAAAACCCCCTT ATT AT GT AGGATT AGGAGT A GAAGCCACACTTAAACGTGGCCCTCTATCTTGTCATACACGACCCCGTGCTCTCACAAT AGGAGATGTGTCTGGAAATGCTTCCTGTCTGATTAGTACCGGGTATAACTTATCTGCTTC TCCTTTT CAGGCT ACTT GT AAT CAGTCCCT GCTT ACTTCCAT AAGCACCT CAGTCT CTT A CCAAGCACCCAACAATACCTGGTTGGCCTGCACCTCAGGTCTCACTCGCTGCATTAATG G AACT G AACCAGG ACCT CTCCTGTGCGTGTT AGTT CAT GT ACTTCCCCAGGT ATATGTG TACAGTGGACCAGAAGGACGACAACTCATCGCTCCCCCTGAGTTACATCCCAGGTTGCA CCAAGCTGTCCCACTTCTGGTTCCCCTATTGGCTGGTCTTAGCATAGCTGGATCAGCAG CCATT GGT ACGGCTGCCCTGGTTCAAGGAGAAACTGGACT AAT ATCCCT GTCTCAACAG GT GG AT GCT G ATTTT AGT AACCTCCAGTCT GCCAT AGAT AT ACT ACATTCCC AGGT AG AG TCTCTGGCT G AAGT AGTT CTT CAAAACTGCCG ATGCTT AGAT CTGCT ATTCCTCTCT CAA GGAGGTTT AT GT GCAGCTCT AGGAGAAAGTT GTTGCTTCT ATGCCAATCAATCT GGAGT CAT AAAAGGT ACAGT AAAAAAAGTTCG AG AAAAT CT AGAT AGGCACCAACAAG AACG AG AAAAT AACATCCCCT GGT ATCAAAGCAT GTTT AACT GGAACCCATGGCT AACT ACTTT AA TCACTGGGTTAGCTGGACCTCTCCTCATCCTACTATTAAGTTTAATTTTTGGGCCTTGTA T ATT AAATTCGTTT CTT AATTTT AT AAAACAACGCAT AGCTTCT GT CAAACTT ACGTAT CTT AAG ACT C AAT AT G AC ACCCTT GTT AAT AACT G A

SEQ ID NO: 4 H. sapiens DNA

>HERV W Env / Syncytin 1 (T0264)

AT GGCCCTCCCTT AT CAT ATTTTT CT CTTT ACT GTT CTTTT ACCCT CTTT C ACT CT C ACT G CACCCCCTCCATGCCGCT GT AT G ACCAGT AGCTCCCCTT ACCAAG AGTTT CT AT GG AGA AT GCAGCGTCCCGG AAAT ATT GATGCCCCATCGT AT AGG AGTCTTT CT AAGGG AACCCC CACCTTCACT GCCCACACCCAT ATGCCCCGCAACT GCT ATCACTCT GCCACTCTTTGCA TGCAT GCAAAT ACTCATT ATT GGACAGGAAAAAT GATT AATCCT AGTT GTCCTGGAGGAC TTGGAGTCACT GTCT GTTGGACTT ACTTCACCCAAACT GGT AT GTCT GAT GGGGGTGGA GTTCAAGATCAGGCAAGAGAAAAACATGTAAAAGAAGTAATCTCCCAACTCACCCGGGT ACATGGCACCTCTAGCCCCTACAAAGGACTAGATCTCTCAAAACTACATGAAACCCTCC GT ACCCAT ACTCGCCTGGT AAGCCT ATTT AAT ACCACCCTCACTGGGCTCCAT GAGGTC TCGGCCCAAAACCCT ACT AACT GTTGGAT AT GCCTCCCCCT GAACTTCAGGCCAT AT GT TTCAATCCCT GT ACCT GAACAATGGAACAACTT CAGCACAGAAAT AAACACCACTTCCGT TTT AGT AGGACCT CTT GTTTCCAATCT GG AAAT AACCCAT ACCT CAAACCT CACCT GTGT AAAATTT AGCAAT ACT ACAT AC ACAACC AACTCCCAATGCAT CAGGT GGGTAACTCCTCC CACACAAATAGTCTGCCTACCCTCAGGAATATTTTTTGTCTGTGGTACCTCAGCCTATCG TT GTTT GAAT GGCT CTT CAG AAT CT AT GTGCTTCCT CT CATT CTT AGTGCCCCCTAT G AC CAT CT AC ACT G AACAAGATTT AT ACAGTT AT GTCAT AT CT AAGCCCCGC AACAAAAG AGT ACCCATTCTTCCTTTT GTT AT AGGAGCAGGAGT GCT AGGTGCACT AGGT ACTGGCATT G GCGGTAT CACAACCT CT ACT CAGTT CT ACT ACAAACT AT CT CAAG AACT AAATGGGG ACA TGGAACGGGTCGCCGACTCCCTGGTCACCTTGCAAGATCAACTTAACTCCCTAGCAGCA GT AGTCCTTCAAAATCGAAGAGCTTT AGACTT GCT AACCGCT GAAAGAGGGGGAACCT G TTT ATTTTT AGGGG AAG AATGCT GTT ATT AT GTT AAT CAATCCGG AATCGTCACT G AG AA AGTTAAAGAAATTCGAGATCGAATACAACGTAGAGCAGAGGAGCTTCGAAACACTGGAC CCTGGGGCCTCCTCAGCCAATGGATGCCCTGGATTCTCCCCTTCTTAGGACCTCTAGCA GCT AT AAT ATTGCT ACTCCT CTTTGGACCCT GTAT CTTT AACCTCCTT GTT AACTTT GTCT CTTCCAG AATCG AAGCT GT AAAACT ACAAATGGAGCCCAAG ATGCAGTCC AAGACT AAG AT CT ACCGCAG ACCCCT GG ACCGGCCT GCT AGCCCACGAT CT GAT GTT AAT G ACAT CAA AGGCACCCCTCCTGAGGAAATCTCAGCTGCACAACCTCTACTACGCCCCAATTCAGCAG GAAGCAGTTAG

SEQ ID NO: 5 H. sapiens DNA

>HERV FRD Env /Syncytin2 (NM_207582.3)

ATGGGCCTGCTCCTGCTGGTTCTCATTCTCACGCCTTCACTAGCAGCCTACCGCCAT CC T G ATTTCCCGTT ATTGG AAAAAGCT CAGCAACT GCTCC AAAGT ACAGG ATCCCCTT ACTC CACCAATTGCTGGTT AT GT ACT AGCTCTTCCACT GAAACACCAGGGACAGCTT ATCCAG CCTCGCCCAGAGAATGGACAAGCAT AGAGGCGGAATT ACAT ATTTCCT ATCGAT GGGAC CCT AAT CT G AAAGG ACT GAT G AGGCCT GCAAAT AGTCTT CTTT CAAC AGT AAAGC AAGAT TTCCCTGATATCCGCCAGAAACCTCCCATTTTCGGACCCATCTTTACTAATATCAACCTA ATGGGAATAGCCCCTATTTGTGTTATGGCCAAAAGGAAAAATGGAACAAATGTAGGCAC T CTTCCAAGT ACAGTCTGT AAT GTT ACTTT CACT GT AG ATT CT AACCAACAG ACTT ACCAA ACATACACCCACAACCAATTCCGCCATCAACCAAGATTCCCCAAACCTCCAAATATTACT TTTCCTCAGGGAACTTTGCTAGATAAATCCAGCCGGTTTTGCCAGGGACGCCCAAGCTC ATGCAGTACTCGAAACTTCTGGTTCCGGCCTGCTGATTATAACCAATGTCTGCAAATTTC CAACCTCAGCT CT ACAGCGG AATGGGTT CT ATT GG ACC AAACTCGAAATT CT CTTTTTT G GGAAAATAAAACCAAGGGAGCTAACCAGAGCCAAACACCCTGCGTCCAAGTCTTAGCA GGCAT GACT AT AGCCACCAGCT ACCTGGGCAT ATCAGCAGTCTCAGAATTTTTT GGAAC CTCCCTCACCCCCTT ATTT CATTTCCAT ATCTCT ACATGCCTT AAAACT CAAGG AGCCTTT T AT ATTT GTGGCCAGTCGATT CACCAAT GCCTCCCCAGT AACT GG ACT GG AACTT GT AC CATAGGCTATGTAACCCCAGACATCTTCATAGCCCCTGGCAATCTCTCTCTTCCAATACC AATCTATGGGAATTCCCCGTTGCCCAGGGTGAGGAGGGCAATCCATTTCATTCCCCTTC TCGCGGGACTCGGCATTCTAGCTGGTACGGGAACCGGAATTGCTGGAATCACAAAAGC TTCCCTCACCT AT AGCCAGCTCTCAAAGGAAAT AGCCAACAACATT GACACCAT GGCT A AAGCCTTAACGACCATGCAAGAACAAATCGACTCTTTAGCAGCCGTAGTCCTTCAAAATC GTCGAGGACT AGACAT GTT AACGGCAGCACAGGGAGGAATTT GTTT GGCCTT AGAT GAA AAAT GTT GCTTTT GGGT AAAT CAAT CAGGAAAAGT ACAAGACAACAT CAG AC AACTCCT A AATCAAGCCTCCAGTTTACGGGAACGAGCCACTCAGGGTTGGTTAAATTGGGAAGGAAC TTGGAAATGGTTCTCTTGGGTTCTTCCCCTTACAGGCCCACTTGTTAGTCTCCTACTTTT GCTCCTTTTT GGTCC AT GTCTCCT AAAT CT AAT AACCC AATTT GT CTCCT CTCGCCTT CA GGCCATAAAGCTCCAGACGAATCTCAGTGCAGGACGCCATCCTCGCAATATTCAAGAGT CACCCTTCTAA

SEQ ID NO: 6 H. sapiens DNA

>HERV R Env /ERV3 (AAA88027)

AT GACT AAAACCCT GTT GT ATCACACTT ATT AT GAGT GTGCTGGGACCTGCCT AGGAACT T GT ACTCACAACCAGACAACCT ACTCAGTCT GT GACCCAGGAAGGGGCCAGCCTT AT GT GTGTTATGACCCTAAGTCTTCACCTGGGATCTGGTTTGAAATTCATGTCGGGTCAAAGG AAGGGGATCTTCTAAACCAAACCAAGGTATTTCCCTCTGGCAAGGATGTCGTATCCTTAT ACTTT GAT GTTTGCCAG AT AGT ATCCAT GGGCT CACTCTTTCCCGT AAT CTT CAGTTCCA TGGAGT ACT AT AGT AGCTGCCAT AAAAAT AGGT ATGCACACCCT GCTT GTTCCACCGATT CCCCAGT AACAACTTGCTGGGACTGCACAACGTGGTCCACT AACCAACAATCACT AGGG CCAATT ATGCTT ACCAAAAT ACCATT AGAACCAGATT GT AAAACAAGCACTTGCAATTCT GT AAATCTT ACCAT CTT AGAGCCAGAT CAGCCC AT AT GG ACAACAGGTTT AAAG ACACC GCT AGGGGCACGAGTCAGCGAT GAAGAAATTGGCCCAGGAGCCT AT GTCT ATCT AT AT A T CAT AAAG AAAACTCGG ACCCGCT CAACCCAACAGTTGCGAGTTTTT GAGTCATTCT AT G AGCAT GTT AACCAGAAATTGCCT GAGCCCCCTCCCTTGGCCAGT AATTT ATTCGCCCAA CTGGCT GAAAACAT AGCCAGCAGCCT GCACGTT GCTTCAT GTT AT GTCT GTGGGGGAAT GAA CAT GGGAGACCAAT GGCCATGGGAAGCAAGGGAACT AAT GCCCCAAGAT AATTTC ACACTAACCGCCTCTTCCCTCGAACCTGCACCATCAAGTCAGAGCATCTGGTTCTTAAA AACCTCCATTATTGGAAAATTCTGTATTGCTCGCTGGGGAAAGGCCTTTACAGACCCAG T AGGAGAGTT AACTT GCCT AGGACAACAAT ATT ACAACGAGACACT AGGAAAGACTTT AT GGAGGGGCAAAAGCAATAATTCTGAATCACCACACCCAAGCCCATTCTCTCGTTTCCCA T CTTT AAACCATT CTT GGT ACCAACTT G AAGCTCCAAAT ACCTGGC AGGC ACCCTCT GG CCTCT ACTGGATCT GT GGGCCACAAGCAT ATCGACAACTGCCAGCT AAATGGTCAGGG GCCT GT GT ACTGGGGACAATT AGGCCGTCCTTCTTCCT AATGCCCCT AAAACAGGGAGA AGCCTTAGGATACCCCATCTATGATGAAACTAAAAGGAAAAGCAAAAGAGGCATAACTAT AGGAGATT GGAAGGACAGT GAATGGCCTCCT GAAAGAAT AATTCAAT ATT ATGGCCCAG CCACCTGGGCAGAAGAT GGAAT GTGGGGAT ACCGCACCCCAGTTT ACATGCTT AACCG CATT AT AAGATT GCAGGCAGT ACT AGAAATCATT ACCAAT GAAACTGCAGGGGCCTT GA ATCT GCTTGCCCAGCAAGCCACAAAAAT GAGAAAT GTCATTT ATCAAAAT AGACT GGCCT T AGACT ACCTCCT AGCCCAGGAAGAGGGAGT ATGCGGAAAGTTCAGCCTT ACT AACTGC TGCCTGGAACTT GAT GACGAAGGAAAGGTT ATCAAAGAAAT AACTGCT AAAATCCAAAA GTTAGCTCACATCCCAGTTCAGACTTGGAAAGGATAG

SEC ID NO: 7 H. sapiens DNA

>HERV R(b) Env (AC093488)

AT GG ATCCACT ACACACGATT G AAAAAGTTCCT GC AAGAAG AAAC ATCCACG ACAG AGG ACACCAAGGCCACCGAATGGGAGAT GGAACCCCT GGAAGGCCT AAGATTTCT GTTCAA CAAAT G ACAAG ATTTTCCCTT AT AAT ATTTTTCCTTT CTGCTCCTTTT GTT GTT AATGCCT C T ACCTCT AACGTTTTCCT ACAATGGGCACACAGTT ATGCAGATGGCTT ACAACAAGGAG ACCCTTGCTGGGTCTGTGGTTCGTTACCCGTCACTAACACCATGGAGCTACCTTGGTGG GTCTCCCCGCTACAAGGGAAAGACTGGGTTTTTTTTCAAAGCTTTATAGGGGATCTTAAA CAATGGACAGGGGCACAGATGACTGGGGT AACT AGAAAAAACATTTCAGAATGGCCT AT AAAT AAAACTTT AAAT GAGCCAGGGCAT GAT AAACCATTCTCAGT AAAT GAGACAAGGGA T AAAGT AAT AGCCTTTGCCATCCCCTT GTTGGAT ACCAAGGT GTTT GTCCAGACTTCCAG ACCTCAGAACACTCAATATAGAAATGGGTTTCTCCAGATATGGGACGGGTTCATTTGGC T GACAGCCACT AAGGGACACTT AAGCCAGAT AGCTCCCTT AT GCT GGGAGCAAAGAAAT CACTCCCTT GAT AACTGGCCAAACACAACTCGT GTT ATGGGATGGATTCCACCTGGACA GTGCCGACAT ACT AT ACT GTT ACAACAGAGGGACCT ATTTGCCACAGACT GGTCTCAGC AACCTGGCTTGAATTGGTATGCTCCCAACGGAACCCAGTGGCTCTGCAGCCCAAACTTA TGGCCTTGGCTTCCCTCAGGTTGGTTAGGATGCTGCACTCTAGGTATTCCCTGGGCACA AGGACGCTGGGTAAAAACCATGGAAGTCTATCCTTATCTTCCACATGTGGTTAACCAAG GGACT AGGGCCATT GTT C ACAGG AAT GAT CACCT ACCCACAAT CTTT ATGCCCT CAGT A GGTTT AGGAACT GT AAT ACAGCACATAGAGGCTCT AGCCAATTTT ACCCAACGGGCCCT AAAT GACAGCCTCCAAAGT ATTT CT CT CAT GAATGCT G AAGT GT ATT AT ATGCACGAGG A CATCTT ACAAAACCGAATGGCCCT AGAT ATTTT AACTGCGGCT GAAGGAGGAACCT GT G CCCT CAT C AAAACT G AAT GTTGTGTGTAT ATTCCCAAT AACT CT AG AAACATTTCCTTGG CCTTAGAGGATACATGTCGGCAAATCCAAGTCATCTCCAGCTCTGCACTGTCACTCCAT G ACTGG AT AGCATCTCAGTTT AGTGGAAG ACCTTCCT GGTGGC AG AAAATCCTCATT GT CCTTGCCACCCTCTGGAGCGT AGGCAT AGCACT GT GTT GTGGACT GT ATTTTT GTCGCA T GTTTTCCCAACACATTCCCCAAACT CATTCGATT AT ATTT CAACAGG AACTTCCCTT GAG CCCCCCAAGTCAGGAGCATTACCAGAGCCAAAGAGACATCTTCCACTCTAACGCCCCCT GA

SEQ ID NO: 8 H. sapiens DNA

>HERV F(c)2 Env (AC016222)

AT GAATTCTCCAT GT G ACAGGCTCCAACAATTT ATT CAGGTT CTT CTCG AGG AAAGCTGG

TCATTCCCTAGTTTTGCTAACACCCTTCACTGGCCTGAAAATCTGTTGTCCTATATA GAC

GAACTGGTATGGCAAGGCTCCCTCCAGAACTTTCACCAACATGAAGTTCGCTTTGAC AA

GCCCCCTCTCAGACTCCCTCTCACTGGGTTTTCTTCCCTCACTGAGAATTGGAGTTC CA

GACAGGCAGTGTCCTCTAGACTAGTAGCCACGGCAGCATCCCCGCCAGCAGGGTGTC A

GGCACCCATAGCTTTCCTAGGTCTAAAATTCTCTTCCCTAGGCCCGGCTAGAAAAAA CC

CTGCACTTTGCTTCCTCTATGATCAAAGTAACTCCAAATGCAATACCAGCTGGGTCA AAG

AAAAT GT AGGCT GTCCGTGGCACTGGTGCAAT ATCCAT GAGGCATT AATTCGT ACT GAA

AAAGGATCT GACCCAAT GTTCT AT GTCAAT ACCTCCACTGGAGGACGGGACGGCTTT AA

CGGATTT AACCTCCAAATTTCT GACCCTTGGGACCCCCGCTGGGCCTCCGGT GT AGAT G

GAGGACT AT AT GAGCACAAAACTTTT AT GT ATCCAGT AGCT AAGATCCGCATTGCCAGG

ACCCTTAAAACCACTGTCACAGGGTTATCCGACTTAGCCTCCTCAATCCAGTCAGCC GA

GAAAGAGCTTACCAGCCAGCTTCAACCGGCAGCTGACCAGGCCAAGTCCTCCCGCTT C

TCGTGGTTAACTTTAATCTCAGAAGGTGCACAATTGCTCCAATCCACAGGGGTACAA AA

CCTCTCCCACTGCTTCCTCTGTGCAGCCCTCAGAAGACCTCCATTAGTAGCAGTTCC TC

TCCCT ACCCCCTTT AATT AT ACT AT AAATT CAT CAACCCCT AT ACCACCGGTCCCAAAAG

GACAGGTCCCACTATTCTCAGACCCTATAAGACATAAGTTCCCATTCTGTTACTCTA CCC

CAAATGCCTCTT GGT GT AACCAGACT AGGATGCTT ACCAGCACCCCGGCACCGCCCAG

AGGCTACTTCTGGTGTAACTCCACGCTAACTAAAGTTCTTAACTCAACTGGTAATCA CAC

CTTGTGCTTACCCATCTCTCTCATCCCTGGCCTGACCCTATATAGTCAGGATGAACT TAG

CCATCTGCT AGCCT GGACCGAGCCAAGGCCACAAAAT AAAAGCAAAT GGGCT ATTTTCT

TACCCTTAGTACTAGGCATCTCCTTAGCCTCCTCCTTAGTGGCATCAGGGCTAGGAA AA

GGAGCCCTCACCCACTCAATCCAAACATCTCAAGATCTGTCTACTCACCTGCAGTTG GC

CATTGAGGCATCGGCCGAGTCCCTGGACTCCCTACAGCGACAGATCACTACAGTAGC A

CAGGTCGCAGCACAGAACAGGCAGGCCTTAGACTTGCTTATGGCAGAAAAAGGAAGG A

CAT GTTT ATTCTT ACAGGAAG AAT GCTGCT ATT AT CT C AAT G AGTCAGGGGT AGTT GAGA

ACAGTTTACAAACTTTAAAAAAAAAAAAAAGCTCCAAGAGGAGTTAA

SEC ID NO: 9 H. sapiens DNA

>HERV F(c)1 Env (AL354685)

ATGGCCAGACCTTCCCCACTATGCCTCCTACTCCTCCTGACCCTCCTAACCCCCATA GT

GCCCAGTAACTCCCTCCT AACT G AACCCCCGTTCCG ATGGAGGTT CT ACCTGCAT GAGA

CTTGGACCCAAGGCAACCGGCTCTCCACT GTCACACT GGCAACGGT GGACTGCCAACC

TCACGGTTGTCAGGCCCAAGTAACTTTTAACTTCACTTCCTTTAAAAGTGTTCTGCG GGG

CTGGTCCAATCCCACCATCTGCTTTGTCTATGATCAAACACACAGCAACTGCCGCGA CT

ATT GGGTGGACACAAACGGAGGATGCCCCT AT GCCT ATT GTCGT ATGCAT GT GACCCAG

CTCCATACCGCCAAGAAACTCCAACACACCTATCGCCTGACATCTGATGGAAGGACA AC

TTACTTCCTGACCATCCCAGACCCATGGGATTCTCGGTGGGTCAGTGGAGTCACTGG TC

GACT GT ACCGGT GGCCCACCGACTCCT ACCCAGTTGGCAAACTCCGGAT ATTCCT GACT

T AT AT ACGAGTT AT CCCCCAGGTTTT GTCT AATTT AAAGGACCAAGCAGACAACATT AAG

CATCAGGAAGAGGTCATCAATACTTTGGTGCAGTCCCATCCGAAGGCTGACATGGTC AC

CT AT GAT GACAAGGCT GAGGCAGGACCGTTTTCATGGAT AACCCT AGTCCGCCACGGG

GCTCGCCTTGTTAATATGGCAGGCCTAGTTAATCTCTCCCACTGTTTCCTTTGCACC GCC

CTCAGCCAACCACCACT AGTAGCT GT ACCCCT ACCCCAGGCTTTT AACACCTCTGGT AA

CCACACTGCCCACCCTTCCGGCGTCTTCTCTGAGCAGGTCCCTCTTTTCCGAGACCC CC

TCCAGCCCCAGTTCCCCTTCTGCTACACCACTCCTAACTCATCCTGGTGCAACCAGA CC

TATTCTGGCTCCCTATCTAACCTCTCTGCACCGGCAGGTGGCTACTTCTGGTGTAAC TT

CACCCTT ACAAAACAT CTT AAT ATTTCCTCT AACAAT ACCCTTT CT AGAAACTT ATGCCTC

CCCATCTCTCTGGTGCCTCGACTCACTCTGTACAGCGAGGCTGAACTCTCTTCCCTT GT

CAACCCGCCTATGCGTCAGAAGCGGGCCGTTTTCCCACCGCTGGTAATAGGTGTCTC C

TT GACCTCCTCACTT GTTGCCTCCGGGCTGGGCACAGGTGCT ATT GT ACATTTCAT AAG

CTCTTCCCAAGATCTCTCTATTAAGCTCCAGATGGCCATCGAAGCCTCAGCCGAATC CT

T AGCCTCTCT ACAGAGACAGATT ACGTCT GTGGCCAAGGTGGCCATGCAGAACCGGAG

AGCCCTAGATCTCCTCACAGCCGACAAAGGCGGAACCTGCATGTTTCTCGGGGAAGA G

TGCTGTT ATT ACAT CAAT G AAT CAGGCTT AGT AG AAACCAGCCTCCT CACCCTT GAT AAA

ATCCGGGACGGTCTCCATCGACCCTCCTCAACTCCCAACTATGGAGGAGGGTGGTGG C

AATCCCCTTT AACCACTTGG ATT ATCCCTTT CAT AAGCCCCATCCT AAT CATTTGCCTTTT

ACTTCTCATAGCCCCCTGTGTCCTCAAGTTCATCAAAAACCGCATCAGCGAAGTCTC CC

GGGTGACGGTCAACCAAATGTTACTACACCCTTACTCCCGTCTTCCGACCTCCGAAG AC

CACTATGACGACGCCCTCACTCAGCAGGAAGCAGCCAGATGATTACGTCGCCCCTTT TT

CTT ACAGT AT GAGGTCGGAAT GTT AGGCAGGTCACCCAAGAT GGCT GTTCCCCCAGGA

CCCAAGATGGCGGCACGAACCCCTTCTTCCCCGCCCCCCCCACCGCTTGGAGTCTCC C

ACCAGATTTTCCCGCCCGACGGGCACTTTCCGATGACAGCAGCCCCGAGAAGTCGAA A

CCT ATCCCAG AAAACCG AAACTT ACT AA

SEQ ID NO: 10 H. sapiens DNA

>HERV E Env (AY208746)

AT GAGGAAGCTCATCGT GGGATTCATTTTTCTT ACATTTTGGACTT ACACAGT AAGGGCT TCAACTGACCTTACTCAAACTGGGGACTGTTCCCAGAGTATTCATCAGGTCACCGAGGT AGGACAGCAAATT AAAACAAACTTTCT GTTCT AT AGTT ATT AT GAAT GT ATGGGAACATT A AAAGAAACTT GTTT GT AT AATGCCACTCAGT ACAAGGT AT GT AGCCCAGGAAAT GACCG ACCCGAT GT GT GTT AT AACCCATCT GAGCCCCCTGCAACCACCGTTTTT GAAAT AAGATT AAGAACTGGCCTTTTCCT AGGT GACACAAGT AAAAT AAT AACT AGAACAGT AGAAAAAGG AATCCCC AAACAAAT AACTTT AAGATTT G ATGCTCGT GC AGCCATT AAT AGT AACAAGTT AGGAACACGAT GTGGTTCTCTT AACT GGGAAAGGAGCT ACACAGT ACAAAAT AAAT AT G TTTGTCATGAGTCAGGGGTTTGTGAAAATTGTGCCTTTTGGCCATGTGTTATTTGGGCTA CTTGGAAAAAGAACAAAAAGGACCCTGTTCATCTTCAGAAGGGGGAAGCCAACCCCTCC TGT GCTGCCGGTCACT GT AACCCACT AGAACT AAT AATT ACC AATCCCCT AGATCCTCCT TGGAAAAAGGGAGAACGT GT AACCCTGGGGATCGATGGGACAGGGTT AAACCCCCAAG TTGCCATTTTAGTTAGAGGGGAAGTCCACAAGCGCTCTCCCAAACCAGTGTTTCAAACC TTTT AT GAGGAGCT GAATCTGCCAGCACCAGAACTTCCGAAAAAGACAAAAAGTTT GTTT CTCCAATT AGCAGG AAAT GTAGCT CATT CACTT AAT GTT ACTTCCT GTT AT GT ATGCAGG GGAACCACTATCGGAGACCGATGGCCTTGGGAAGCCCGAGAGTTGGTGCCTACTGATC CAGCTCCTGATATAATTCCAGTTCAGAAGGCCCAAGCTAGCAACTTCTGGGTCCTAAAA ACCT CAATT ATT GG AC AAT ACT GTAT AGCT AGAG AAGGG AAAG AATTT ATCGTCCCTGTA GGAAAGCTT AATT GT AT AGGACAGAAGTT GT ACAACAGCACAACAAAGACAATT ACTTGG TGGGGCCT AAACCACACT G AAAAG AACCCATTT AGT AAATTTT CT AAATT AAAAACTGCC TGGGCTCATCCAGAATCTCATCAGGACTGGACGGCTCCCACCGGACTATACCGGATAT GTGGGCACACAGCCTACATTCAGTTACCTAATAAATGGGCAGGCAGTTGTGTTATTGGC ACT ATT AAGCT GTCCTTTTTCTT ATT ACCCAT AAAAACGGGT GAGCTCCT AGGTTTCCGT GTCT AT ACCTCCCGAGAAAAGAGAGGCAT AGTT AT AGGAAACTGGAAAGAT AAT GAGT G GCCCCCT GAAAGGATCAT ACAAT ATT ATGGGCCT GCCACAT GGGT ACAAGACGGCTCAT GGGGATACCAAACCCCCATCTACATGCTCAATCAGATCATACGGTTGCAGACCGTCTTA GAAATAATTACTAATGAAACTGGCAGAGCTTTGACTGTTTTAGCTCGGCAGGAAACCCAA AT GAGGAATGCT ATCT ATCAGAAT AGACT GGCCTTGGACT ACTTGCTGGCAGCT GAAGG AGGAGTTT GTGGAAAATTT AACTT AACCAATT GCTGCCT ACAAAT AGAT GATCAAGGACA GGT GATT GAAAACAT AGTCAGGGACAT GACAAAGTTGGCACACACGCCT AT ACAGGTTT GGCACAAGTTT GATCCT GAGTCTTT ATTTGGAAAAT GGTTTCCAGCT AT AGGAGGATTT A AAACCCTCATT GT AGGT GT ATT GCT AGT AAT AAGAACTT GCTTGCTGCTCCCCT GT GT AT T ACCCTTGCTTTTT CAAAT GAT AAAAGGT ATT GTTGCT ACTTTGGTT CAT CAG AAAACTT C AGCACACGT G AATT AT AT GAAT CACT ATCGCT CT ATCTCGCAAAG AG ACT CAAAAAGT GA GGAT GAGAGT GAGAACTCCCACT AA

SEQ ID NO: 11 H. sapiens DNA

>HERV P(b1) Env /HERV IP (DQ247958)

ATGGACCCATCACACCCGAGTCAAGAAAGCACCGCCCCCTCCAGCGTCATGGGCCAT A GTCCCAGGGG AAAATCCT ACCAAACT AAAGCT AAGGAAAGTTT AATT CT CTTT CAT CT AT TCTGTT ACTCCTT CTT CTTTCCTT GTGCT CTTGCT AGCCACCT CATT ATT AACGT AACTAG AT CAG ACT CACCCCAG ACCATT ACCTTCGAT GCTT GTTT AGTT AT ACCTT GT GGGGAT CT CCAAAGCCAGAGACAGCTTGCAGCAGCAGAGAAATATCTCTGCCCCTCCGAAGCAGAT GCTTCT ACCTT GTTT AGCTTTCCGTTTT GTCAT ACTT GGGAAT AT GTCGTTTGGACCACT CAACGTCAAGATTGGGTCCCCTCACAGGATTTCCCGCTAGCGGTTCTAAAGCCCTATAT CCATTTT ACT AAAGGAATTGCCCCTCCCAATT GTCGAT AT AACCAAT GT AACCCGGTGCA AATTTCCATCACCATCCCAACTCTCCAAGATTCCTCCCCCACCCTAAACCGTTTCTATGG T AT GGGAGCAGAT GT AAGAGGGAAAGACCCCAT AGGATTCTTCGAGTT GCACCTCAGT A CATCTCCATCCCTCATATCTCCACGTCTATCCTCTTCTACACCTGCTAACCAGACCATTG T CT CTT CAT CT AAT G ACAAAAGCAAAGT AGCT ATT GT AG AGGTT AAAAATTT AAAACAAAC ACT GACAATT GAAACAGGATACAAAGAAACAAATGCCTGGAT GGAATGGATT GAAT ATTC CGTTCGCAGTCTAAACAAAAGCGACTGTTACGCTTGTGCGCAAGGTAGGCCAGAGGCC CAAGTCGTCCCCTTTCCACTTGGATGGTCTTCTGACCAACCGGGCATGGGCTGCATGGT GGCTCTTTTCCAACACCCTACAGCCTGGGATAGTGAGTTCTGTCGAACTCTCTCTGTGC TATTCCCTGAAACTCAACACCTTGAGGGTGAGCCCCCGAGGGCCATCCAGCCTCCATCT CCAGATGCCAAGTTTACTTCCTGTCTCTCACGACAGGGAAAAAATTTGGAGTTTCTTGG GGACCTAAAGGGATGCAGTGAGCTTAAGTCTTTCCAAGAGCTTACCAATCAGTCTGCAC TT GTT CAT GCCCGAGCT GAT GTATGGTGGT ATTGTGGT GGTCACCTGCT AG ACACT CT G CCAAGTAACTGGAGTGGTACTTGTGCTCTAATTCAATTGGCCATCCCTTTCACCCTGGC ATTTCAACAACCAGAAAAAAAGAAACCACAACGCCGTAAAACAAGAGAGGCCCCTCAAG GATCTTTCGACTCTCATGTCTATGTAGATGAAATTGGAGTCCCACAGGGGGTACCTGAT AGATTCAAAGCCCGAGACCCAGT AGCT GCAGGATTT GAATCATT ATTTCCAAT GGT AGC T ATT AAT AAAAAT GT AGCTTGGAT AAATT ACATCT ATT AT AACCAGCAGCGATTT ATTAATT ACACT AGGGAT GCT ATCCAAGGAAT AGCT GAA CAATT AGGGCCT ACT AGCCAAAT GGCT TGGGAAAACAGAATGGCCTT AGAT AT GAT ATT AGCAGAAAAAGGT GGAGTTT GT GTT AT GAT AGGAACCCAATGCTGCACCT ACATTCCCAACAAT ACAGCTCCT GAT GGAACAATT A CAAAAGCTTT ACAAGGTCTT ACCTCCTT AT CAG AT G AATT AGCCACAAATT CTGGG AT AA CTGACCCTTTCACAGGATGGTTAGGGCAATGGTTTGGTAAATGGAAAGGACTCATGGCC TCTATTGTTACCTCTCTCGCAATCGCAATAGCTGTGCTTATTCTTGTTGGATGCTGCATC ATGCCCT GCATTCGTGGACT AGTCC AAAG ACTT AT AG AG ACAGCT AGT AACAAAACCTT CCCTAGTTCTTCCCAATCCTATAGTAACAAATTCTTCCCCGTGAACGAACACGAAATCCG AAT CAT ATT AG AT AGGTTT AAAGCAGAAC AT GTATAA

SEQ ID NO: 12 H. sapiens DNA

>HERV V Env (NM_001191055)

AT GACAGAGAAATTCCTTTTCCTTT AT CTTTCCCTCCTTCCCATGCCCCT ACT CT CAC AG GCAC AGT GG AAT G AAAATTCCCTT GT CAGTTTTTCCAAAAT AATT GCTTCGGG AAACCAT CTAAGCAACTGTTGGATCTGCCACAACTTCATCACCAGGTCCTCATCTTACCAATATATT TTGGT AAGAAATTTTTCTTT AAACCT AACATTTGGTTCAGGAATCCCT GAAGGCCAACAT AAATCTGTTCCGCTCCAGGTTTCGCTTGCTAACTCAGCGCACCAAGTCCCCTGCCTGGA T CT CACTCCACCTTT CAAT CAAAGCT CT AAAACTTCTTT CT ATTT CT ACAACTGCT CTT CT CT AAACCAAACCT GTT GTCCATGCCCT GAAGGACACT GT GACAGGAAGAACACCTCT GA GGAGGGATTCCCCAGTCCCACCATCCATCCCATGAGCTTCTCCCCAGCAGGCTGCCAC CCT AACTT GACT CACTGGT GTCC AGCT AAACAAAT GAACGATT ATCGAG ACAAGT CACC CCAAAACCGCT GTGCAGCTTGGGAAGGAAAAGAGCT AATCACATGGAGGGTTCT AT ATT CGCTTCCCAAGGCACACACTGTCCCCACATGGCCAAAATCTACTGTTCCCCTGGGAGG GCCTCTATCCCCTGCATGCAATCAAACTATTCCAGCAGGGTGGAAATCGCAGTTACACA AGTGGTTCGACAGCCACATCCCCCGGTGGGCCTGTACCCCTCCTGGCTATGTATTTTTA TGT GGGCCACAAAAAAAT AAACT GCCCTTT GATGGAAGTCCT AAGAT AACCT ATT CAACC CCCCCTGTGGCAAACCTCTACACTTGCATTAATAACATCCAACATACGGGAGAATGTGC TGTGGGACTTTTGGGACCACGGGGGATAGGTGTGACCATTTATAACACCACCCAACCCA GACAGAAAAGAGCTCTGGGTCT AAT ACTGGCAGGGATGGGTGCGGCCAT AGGAAT GAT CGCCCCATGGGGAGGGTTCACTTATCATGATGTCACCCTCAGAAATCTCTCCAGACAAA T AGACAACAT AGCT AAG AGT ACCAG AG AT AGCATCTCT AAACTCAAGGCCTCCAT AG ATT CT CT AGC AAAT GT AGTCAT GG ACAACAGATT GGCCTT AG ATT ACCT CTT AGCAG AGCAG GGTGGAGTCT GT GCAGT GATCAAT AAATCCT GTTGCGTTT AT GTCAAT AACAGT GGGGC GAT AGAGGAGGAT AT AAAAAAGATCT AT GAT GAGGCT ACGTGGCTCCAT GACTTTGGAA AAGGAGGTGCTTCAGCAAGGGCCATCTGGGAGGCTGTGAAGTCTGCCCTCCCCTCCCT CAACTGGTTT GTCCCTTT ACTGGGACCAGCAACAGTT AT ACTCTT ACTTTTCCTCTTT GG CCCTT GTTT CTTT AATTT ACT GATT AAGT GTGTCT CTT CT AGG AT AAAGCAATTT CACAT G AAGTCCCCCCAAATGGAAAGAT ATCAGCT ATCT GTCATT GGAGGCCCCAGCACCT AT AA GCACATCTCCCCCTT GGAT GCCAGTGGGCAAAGATTCCGGGAAACT AT GGAGGAATTTT CTCTCTGA

SEC ID NO: 13 H. sapiens DNA

>HERV MER34 Env (NM_001242690.1, NM_024534)

AT GGGCTCCCTTTCAAACT ATGCCCTGCTTCAACT AACCCTT ACT GCTTTTTT GACAATT CTAGTACAACCTCAGCACCTGCTTGCTCCAGTTTTCCGGACACTATCTATCTTGACTAAT CAGT CT AATTGCTGGTT AT GT GAACATCT AGAT AAT GCAGAACAACCCGAACT AGTTTTT GTTCCTGCCAGT GCAAGCACCTGGTGGACCT ATTCTGGACAATGGAT GT AT GAAAGGGT GTGGTATCCACAAGCAGAAGTACAGAATCACTCTACTTCCTCCTATCGTAAAGTGACTTG GCACTGGGAAGCCTCCATGGAAGCTCAAGGTCTATCCTTTGCTCAAGTAAGGTTATTGG AGGGAAATTTTTCTCTTTGCGT AGAAAAT AAAAATGGCAGTGGACCCTTCCT AGGT AAT A TACCT AAA CAAT ACTGT AAT CAAAT ACT AT GGTTT GATT CT ACAG AT GGCACCTT CATGC CCTCTAT AGAT GTT ACAAAT G AATCCAGG AACG AT GAT GAT GAT ACAAGT GTTTGCCT AG GCACT AGACAAT GTTCCTGGTTTGCAGGTT GCACAAACCGGACCT GGAACAGCTCAGCT GTTCCCTT GATT GGTCTGCCCAAT ACCCAAG ACT ACAAATGGGT AGATCG AAATT CTGG ATT GACCTGGTCAGGT AAT GACACCT GTCTCT AT AGCTGCCAAAACCAAACCAAAGGCC TTCT GT ACCAGCT ATTTCGCAACCT ATTTTGCTCTT ATGGCCT GACAGAGGCACATGGGA AATGGAGAT GTGCAGATGCCAGCAT AACT AAT GACAAAGGTCAT GATGGACACCGGACC CCCACCTGGTGGCTCACAGGTTCCAATCTGACCTTGTCTGTGAACAACTCTGGCCTCTT TTTTTTGTGCGGCAATGGGGTGTACAAAGGGTTTCCACCTAAATGGTCTGGGCGATGTG G ACTTGGGT AT CTT GT ACCTTCCCT CACCAGAT ACCT CACCTT AAATGCT AGCCAAATT A CAAACCT G AGATCCTT CATT CAT AAAGT AACACCGCAT AG ATGCACCCAAGG AG ACACA GACAATCCACCTCTGTATTGCAACCCCAAGGACAATTCAACAATAAGGGCCCTTTTTCCA AGTTTGGGAACTTATGATTTAGAAAAGGCAATTCTAAACATTTCCAAAGCAATGGAACAG GAATTCAGTGCCACT AAGCAGACCTTGGAAGCACACCAATCAAAAGTT AGCAGTTT AGC CTCTGCATCCCGAAAGGATCATGTCTTGGATATACCGACCACCCAACGACAAACGGCTT GT GG AACT GTTGGC AAACAGT GTTGCCTCT AT AT AAATT ATTCGGAAG AAAT AAAGTCT A AT AT ACAGCGTCTCCACGAAGCATCCGAG AACCT G AAGAAT GT ACCGTT ACTT G ATTGG CAAGGCATATTTGCAAAAGTGGGAGACTGGTTCAGATCATGGGGCTATGTGCTTTTAAT TGTT CTTTT CTGCTT ATT CAT CTTT GTTTT AAT CTATGTTCGT GTCTTTCGCAAAT CTCGCA GATCCCTTAACTCCCAACCTCTGAACCTAGCCTTATCTCCACAGCAATCAGCACAGCTC CTT GTCAGT G AAACTT CAT GTCAAGTTT CAAAT AGGGCAAT G AAGGG ACT AACAACCCAT CAAT AT G ACACAAGTCT ACTTT GA

SEQ ID N0:14 H. sapiens DNA

>HERV-H Gag consensus sequence

ATGGGCAACCTTCCACCCTCCATTCCTCCTTCTTCTCCCTTAGCCTGTGTTCTCAAG AAC

TT AAAACCTCTT CAACT CACACCT GACCT AAAACCT AAAT GCCTT ATTTT CTT CTGCAAT A

CCGCTTGGCCCCAATACAAACTTGACAGTGGCTCTAAATGGCCAGAAAATGGCACTT TC

AATTTTTCCATCCT ACAAG ACCT AAAT AATTTTT GTCG AAAAAT GGGCAAAT GGTCT GAG

GTGCCTGACGTCCAGGCATTTTTCACACATCGTTCCCTCCCTAGTCTCTGTTCCCAA TG

CAACTCCTCCCAAATCTTCCTTCTTTCCCTCCCGCCTGTCCCCTCAGTCCCAACCCC AA

GCGTCGCTGAGTCTTTCCAATCTTCCTTTTCTACAGACCCATCTGACCTCTCCCCTC CTC

CCCAGGCTGCTCATCGCCAGGCCGAGCTAGGTCCCAATTCTTCCTCAGCCTCCGCTC C

TCCACCCTATAATCCTTTTATCACCTCCCCTCCTCACACCCGGTCCGGCTTACAGTT TCG

TTCCGT GACT AGCCCTCCCCCACCTGCCCAGCAATTTCCTCTT AAAAAGGTGGCTGGAG

CT AAAGGCAT AGTCAAGGTT AATGCTCCTTTTT CTTT AT CAG ACCT CTCCCAAAT CAGT C

AGCGTTT AGGCT CTTTTT C AtCAG ACCCCACT AAAT AT AT ACAGG AATTCCAACAT CT AAC

TCTGTCCTACAATTTAACCTGGAGTGACTTAAATGTCATCCTGACTTCTACCCTCTC CCC

AGATGCACAGGAAAGAGTTTTTTCTCTAGCCCAATCTCATGCTGATAACCGCCGGCT tCA

TGAGCCAGACCTCCAGGAAGGCATTAGAGCAGTTCCCCGAGAGGATCCCCAATGGAA C

TACCAGGCAAATTCCCCAGGTATAGCTAAGCAAGATTACATGGTTTCCTGCGTAGTT GA

AGGGCTT AAAAAAGCAGCTT ACAAAGCT ATT AATT AT GACAAACTtAAAGAAACT ACCCAA

GGTAAAGATAAAAACCCAGCCCAGTTCATGGCTCGTTTGGCAGCAACCCTCAGACGC TT

T ACAGCCCT AG ACCCT AAAAGGT CAAAAGGCCGTCTT ATT CT CAAT AT ACATTTT ATT AC

CCAATCT GCTCCCGACATT AAAAAACTCCAAAAATT AAATT CTGGCCCT CAAACCCCACA

ACAGGATTT AATT AACCTCGCCTTCAAGGT GT ACAAT AAT AGAAAAAAAGCAGCCAGAT G

GCAACGCATTTCT GAGTT GCAATTCCTTGCCTCCACT GT GAGACAAACCCCAGCCACAT

CTCCAGCACACAAGAACTTCCAAATGCCTGAACCGCAGCAGCCAGGCATTCCTCCAG AA

CCTCCTCCCCCAGGAGCTTGCT ACAAGT GCCAGAAATCT GGCCACT gggCCAAGGAAT G

CCCGCAGCCCAGGATTCCTCCTAAGCCGTGTCCCATCTGTGCAGGACCCCACTGGAA A

TCAGACTgTtCAACTCACCTGGCAGCCACTCCCAGAGCCCCTGGAACTCTGGCCCAA GG

CTCTCTGACTGACTCCTTCCCAGATCTGCTCGGCTTAGCGGCTGAAGACTGA

SEQ ID NO: 15 H. sapiens DNA

>HERV-K consensus Gag-Pol AT GGGGCAAACT AAAAGT AAAATT AAAAGT AAAT AT GCCTCTT ATCTCAGCTTT ATT AAAA TT CTTTT AAAAAG AGGGGG AGTT AAAGT AT CT ACAAAAAATCT AAT CAAGCT ATTT C AAAT AAT AG AACAATTTTGCCCAT GGTTTCCAGAAC AAGG AACTTT AGAT CT AAAAG ATTGG AA AAGAATTGGT AAGGAACT AAAACAAGCAGGT AGGAAGGGT AAT ATCATTCCACTT ACAG T AT GGAAT GATTGGGCCATT ATT AAAGCAGCTTT AGAACCATTTCAAACAGAAGAAGAT A GCGTTTCAGTTTCTGATGC

CCCTGGAAGCT GT AT AAT AGATT GT AAT GAAAACACAAGGAAAAAATCCCAGAAAGAAAC GGAAGGTTTACATTGCGAATATGTAGCAGAGCCGGTAATGGCTCAGTCAACGCAAAATG TT G ACT AT AAT CAATT ACAGG AGGT GAT AT ATCCT GAAACGTT AAAATT AGAAGG AAAAG GTCCAGAATTAGTGGGGCCATCAGAGTCTAAACCACGAGGCACAAGTCCTCTTCCAGCA GGTCAGGTGCCCGT AACATT ACAACCTCAAAAGCAGGTT AAAGAAAAT AAGACCCAACC GCCAGTAGCCTATCAATACTGGCCTCCGGCTGAACTTCAGTATCGGCCACCCCCAGAAA GTCAGT ATGGAT ATCCAGGAATGCCCCCAGCACCACAGGGCAGGGCGCCAT ACCCTCA GCCGCCCACT AGGAGACTT AATCCT ACGGCACCACCT AGT AGACAGGGT AGT GAATT AC AT GAAATT ATT GAT AAATCAAGAAAGGAAGGAGAT ACT GAGGCAT GGCAATTCCCAGT AA CGTT AGAACCGAT GCCACCTGGAGAAGGAGCCCAAGAGGGAGAGCCTCCCACAGTT GA GGCCAGAT ACAAGTCTTTTTCGAT AAAAAT GCT AAAA GAT AT GAAAGAGGGAGT AAAACA GT ATGG ACCC AACTCCCCTT AT AT G AGG ACATT ATT AG ATTCCATT GCT CATGGACAT AG ACT CATTCCTT AT GATT GGG AG ATT CT GGCAAAATCGT CTCTCT CACCCT CT CAATTTTT A CAATTT AAGACTTGGTGGATT GAT GGGGT ACAAGAACAGGTCCGAAGAAAT AGGGCT GC CAATCCTCCAGTT AACAT AGATGCAGATCAACT ATT AGGAAT AGGTCAAAATTGGAGT AC T ATT AGTCAACAAGCATT AATGCAAAAT GAGGCCATT GAGCAAGTT AGAGCT ATCTGCCT T AGAGCCT GGGAAAAAATCCAAGACCCAGGAAGT ACCT GCCCCTCATTT AAT ACAGT AA GACAAGGTTCAAAAGAGCCCT ATCCT GATTTT GTGGCAAGGCTCCAAGAT GTTGCTCAA AAGTCAATTGCCGAT GAAAAAGCCCGT AAGGTCAT AGTGGAGTT GAT GGCAT AT GAAAA CGCCAATCCTGAGTGTCAATCAGCCATTAAGCCATTAAAAGGAAAGGTTCCTGCAGGAT CAGAT GT AATCTCAGAAT AT GT AAAAGCCT GT GATGGAATCGGAGGAGCT AT GCAT AAA GCT ATGCTT AT GGCTCAAGCAAT AACAGGAGTT GTTTT AGGAGGACAAGTT AGAACATTT GGAGGAAAAT GTT AT AATT GT GGTCAAATTGGTCACTT AAAAAA GAATT GCCCAGTCTT A AACAAACAGAAT AT AACT ATTCAAGCAACT ACAACAGGT AGAGAGCCACCT GACTT AT GT CCAAG AT GT AAAAAAGG AAAAC ATTGGGCT AGTCAAT GTCGTT CT AAATTT GAT AAAAAT GGGCAACCATTGTCGGGAAACGAGCAAAGGGGCCAGCCTCAGGCCCCACAACAAACT GGGGCATTCCCAATTCAGCCATTTGTTCCTCAGGGTTTTCAGGGACAACAACCCCCACT GTCCCAAGT GTTTCAGGGAAT AAGCCAGTT ACCACAAT ACAACAATT GTCCCCCGCCAC AAGCGGCAGT GCAGCAGT AGATTT AT GT ACT AT ACAAGCAGTCTCTCT GCTTCCAGGGG AGCCCCCACAAAAAATCCCCACAGGGGTATATGGCCCCCTGCCTGAGGGGACTGTAGG ACT AAT CTTGGG AAG AT CAAGTCT AAATCT AAAAGGAGTT CAAATT CAT ACTAGTGTGGT T GATT C AG ACT AT AAAGGCGAAATT CAATTGGTT ATT AGCT CTT C AATTCCTTGGAGT GC CAGTCCAGGAGACAGGATTGCTCAATT ATT ACTCCTGCCAT AT ATT AAGGGTGGAAAT A GTGAAATAAAAAGAATAGGAGGGCTTGGAAGCACTGATCCAACAGGAAAGGCTGCATAT TGGGCAAGTCAGGTCT CAGAGAACAG ACCT GTGTGT AAGGCCATT ATT CAAGG AAAACA GTTT GAAGGGTT GGT AGACACT GG AGCAG AT GTCTCT AT CATT GCTTT AAAT CAGT GGC CAAAAAATTGGCCTAAACAAAAGGCTGTTACAGGACTTGTCGGCATAGGCACAGCCTCA GAAGT GT ATCAAAGT ACGGAGATTTT ACATT GCTT AGGGCCAGAT AATCAAGAAAGT ACT GTT CAGCCAAT GATT ACTT C AATTCCT CTT AAT CT GTGGGGTCG AG ATTT ATT ACAACAAT GGGGT GCGGAAATCACCATGCCCGCTCCATT AT AT AGCCCCACGAGTCAAAAAATCAT G ACCAAGATGGGAT AT AT ACCAGGAAAGGGACT AGGGAAAAAT GAAGAT GGCATT AAAGT TCCAGTT GAGGCT AAAAT AAATCAAGAAAGAGAAGGAAT AGGGT ATCC TTTTTaggggcggccactgtagagcctcctaaacccataccattaacttggaaaacagaa aaaccggtgtgggtaaatca gtggccgctaccaaaacaaaaactggaggctttacatttattagcaaatgaacagttaga aaagggtcatattgagcctt cgttctcaccttggaattctcctgtgtttgtaattcagaagaaatcaggcaaatggcgta tgttaactgacttaagggct gtaaacgccgtaattcaacccatggggcctctccaacccgggttgccctctccggccatg atcccaaaagattggccttt aattataattgatctaaaggattgcttttttaccatccctctggcagagcaggattgtga aaaatttgcctttactatac cagccataaataataaagaaccagccaccaggtttcagtggaaagtgttacctcagggaa tgcttaatagtccaactatt tgtcagacttttgtaggtcgagctcttcaaccagttagagaaaagttttcagactgttat attattcattatattgatga tattttatgtgctgcagaaacgaaagataaattaattgactgttatacatttctgcaagc agaggttgccaatgctggac tggcaatagcatctgataagatccaaacctctactccttttcattatttagggatgcaga tagaaaatagaaaaattaag ccacaaaaaatagaaataagaaaagacacattaaaaacactaaatgattttcaaaaatta ctaggagatattaattggat tcggccaactctaggcattcctacttatgccatgtcaaatttgttctctatcttaagagg agactcagacttaaatagta aaagaatgttaaccccagaggcaacaaaagaaattaaattagtggaagaaaaaattcagt cagcgcaaataaatagaata gatcccttagccccactccaacttttgatttttgccactgcacattctccaacaggcatc attattcaaaatactgatct tgtggagtggtcattccttcctcacagtacagttaagacttttacattgtacttggatca aatagctacattaatcggtc agacaagattacgaataataaaattatgtggaaatgacccagacaaaatagttgtccctt taaccaaggaacaagttaga caagcctttatcaattctggtgcatggcagattggtcttgctaattttgtgggaattatt gataatcattacccaaaaac aaagatcttccagttcttaaaattgactacttggattctacctaaaattaccagacgtga acctttagaaaatgctctaa cagtatttactgatggttccagcaatggaaaagcagcttacacagggccgaaagaacgag taatcaaaactccatatcaa tcggctcaaagagcagagttggttgcagtcattacagtgttacaagattttgaccaacct atcaatattatatcagattc tgcatatgtagtacaggctacaagggatgttgagacagctctaattaaatatagcatgga tgatcagttaaaccagctat tcaatttattacaacaaactgtaagaaaaagaaatttcccattttatattactcatattc gagcacacactaatttacca gggcctttgactaaagcaaatgaacaagctgacttactggtatcatctgcactcataaaa gcacaagaacttcatgcttt gactcatgtaaatgcagcaggattaaaaaacaaatttgatgtcacatggaaacaggcaaa agatattgtacaacattgca cccagtgtcaagtcttacacctgcccactcaagaggcaggagttaatcccagaggtctgt gtcctaatgcattatggcaa atggatgtcacgcatgtaccttcatttggaagattatcatatgttcatgtaacagttgat acttattcacatttcatatg ggcaacttgccaaacaggagaaagtacttcccatgttaaaaaacatttattgtcttgttt tgctgtaatgggagttccag aaaaaatcaaaactgacaatggaccaggatattgtagtaaagctttccaaaaattcttaa gtcagtggaaaatttcacat acaacaggaattccttataattcccaaggacaggccatagttgaaagaactaatagaaca ctcaaaactcaattagttaa acaaaaagaagggggagacagtaaggagtgtaccactcctcagatgcaacttaatctagc actctatactttaaattttt taaacatttatagaaatcagactactacttctgcagaacaacatcttactggtaaaaaga acagcccacatgaaggaaaa ctaatttggtggaaagataataaaaataagacatgggaaatagggaaggtgataacgtgg gggagaggttttgcttgtgt ttcaccaggagaaaatcagcttcctgtttggatacccactagacatttgaagttctacaA TGAACCCATCGGAGATGC

AAAGAAAAGCACCTCCGCGGAGACGGAGACACCGCAATCGAGCACCGTTGACTCACA A

GAT G AACAAAATGGT GACGTCAG AAG AACAGAT G AAGTT GCCATCCACCAAG AAGGCA

GAGCCGCCGACTTGGGCACAACT AAAGAAGCT GACGCAGTT AGCT ACAAAAT ATCT AGA

GAACACAAAGGT GACACAAACCCCAGAGAGT ATGCT GCTT GCAGCCTT GAT GATT GT AT

CAATGGTGGTAAGTCTCCCTATGCCTGCAGGAGCAGCTGCAGCTAA

SEQ ID NO: 16 H. sapiens DNA

>HERV-K orico Gag-Pol (codon optimized) gtcgacgagagatcccgagtacgtctacagtcagccttacggtaagcttgtgcgctcgga agaagctagggtgataatgggcca gaccaagagcaagatcaagagcaagtacgccagctacctgagcttcatcaagatcctgct gaagaggggcggagtgaaggt gtccaccaagaacctgatcaagctgttccagatcatcgagcagttctgcccctggttccc cgagcagggcaccctggacctgaag gactggaagcggatcggcaaagagctgaagcaggccggcaggaagggcaacatcatcccc ctgaccgtgtggaacgactg ggccatcatcaaggccgccctggaacccttccagaccgaagaggacagcgtgagcgtgag cgacgcccctggcagctgcatc atcgactgcaacgagaaaacgcgtaagaagagccagaaagagaccgagagcctgcactgc gagtacgtggccgagcccgt gatggcccagagcacccagaacgtggactacaaccagctgcaggaagtgatctaccccga gaccctgaagctggaaggcaa gggccccgaactggtgggccccagcgagagcaagcccaggggcaccagccctctgcctgc cggccaggtgcccgtgaccct gcagccccagaaacaggtgaaagagaacaagacccagccccccgtggcctaccagtactg gccccctgccgagctgcagta ccggcctccccccgagagccagtacggctaccccggcatgccccctgcccctcagggcag agccccctacccccagcctccc accaggcggctgaaccccaccgcccctcccagcaggcagggcagcgagctgcacgagatc atcgacaagagcaggaaag agggcgacaccgaggcctggcagttccctgtgaccctggaacccatgcctcccggcgagg gcgcccaggaaggcgagcccc ccaccgtggaggcccggtacaagagcttcagcatcaagatgctgaaggacatgaaagaag gcgtgaagcagtacggcccca acagcccctacatgcggaccctgctggacagcatcgcccacggccaccggctgatccctt acgactgggagatcctggccaag agcagcctgagccccagccagttcctgcagttcaagacctggtggatcgacggcgtgcag gaacaggtgcggcggaacagg gccgccaacccccccgtgaacatcgacgccgaccagctgctgggcatcggccagaactgg tccaccatcagccagcaggcc ctgatgcagaacgaggccatcgagcaggtgcgggccatctgcctgcgggcctgggagaag atccaggaccccggcagcacc tgccccagcttcaacaccgtgagacagggcagcaaagagccctaccccgacttcgtggcc cggctgcaggacgtggcccaga agagcatcgccgacgagaaggcccggaaggtgatcgtggagctgatggcctacgagaacg ccaaccccgagtgccagagc gccatcaagcccctgaagggcaaggtgccagccggcagcgacgtgatcagcgagtatgtg aaggcctgcgacggcatcggc ggagccatgcacaaggccatgctgatggcccaggccatcaccggcgtggtgctgggcgga caggtgcggaccttcggcggca agtgctacaactgcggccagatcggccacctgaagaaaaactgccccgtgctgaacaagc agaacatcaccatccaggcca ccaccaccggcagagagccccccgacctgtgcccccggtgcaagaagggcaagcactggg ccagccagtgcagaagcaa gttcgataaaaatgggcaaccattgtcgggaaacgagcaaaggggccagcctcaggcccc acaacaaactggggcattccc aattcagccatttgttcctcagggttttcagggacaacaacccccactgtcccaagtgtt tcagggaataagccagttaccacaata caacaattgtcccccgccacaagcggcagtgcagcagtagatctgtgcacaatccaggcc gtgagcctgctgcccggcgagcc tccccagaagatccccaccggcgtgtacggccctctgcccgagggcaccgtgggcctgat cctgggccggtccagcctgaacct gaagggcgtgcagatccacactagtgtggtggacagcgactacaagggcgagatccagct ggtgatcagcagcagcatcccc tggtccgccagccctggcgaccggatcgcccagctgctgctgctgccctacatcaagggc ggcaacagcgagatcaagcggat ^c gg ^c gg ^cc tggg ^ca g ^cacc g ^accccaca gg ^caa gg ^cc g ^cc t ^ac tggg ^cc t ^ccca ggtgt ^cc gag ^aacc gg ^ccc gtgtg ^caa ggccatcatccagggcaagcagttcgagggcctggtggacacaggcgccgacgtgagcat catcgccctgaaccagtggccc aagaactggcccaagcagaaagccgtgaccggcctggtgggcatcgggaccgccagcgag gtgtaccagagcacagagat cctgcactgtctgggccccgacaaccaggaaagcaccgtgcagcccatgatcaccagcat ccccctgaatctgtggggcaggg acctgctgcagcagtggggagccgagatcaccatgcctgcccccctgtacagccccacaa gccagaaaatcatgaccaagat gggctacatccccggcaagggcctgggcaagaacgaggacggcatcaaagtgcccgtgga ggctaaaataaatcaaaaaa gagaaggaatagggtatcctttttaggggcggccactgtagagcctcctaaacccatacc attaacttggaaaacagaaaaacc agtgtgggtaaatcagtggccgctacctaagcagaaactggaagccctgcacctgctggc caacgaacagctggaaaagggc cacatcgagcccagcttcagcccctggaacagccccgtgttcgtgatccagaagaaaagc ggcaagtggcggatgctgaccg acctgcgggccgtgaacgccgtgatccagcccatgggccccctgcagcctggcctgccca gccccgccatgatccccaagga ctggcctctgatcatcatcgatctgaaggactgcttcttcaccatccccctggccgagca ggactgcgagaagttcgcctttaccatc cccgccatcaacaacaaagagcccgccacccggttccagtggaaggtgctgccccagggc atgctgaacagccccaccatct gccagaccttcgtgggcagagctctgcagccagtgagagagaagtttagcgactgctaca tcatccactacatcgacgacatcct gtgtgccgccgagaccaaggacaagctgatcgattgctacaccttcctgcaggccgaggt ggccaatgccggcctggccatcg ccagcgacaagatccagaccagcacccccttccactacctgggcatgcagatcgagaacc ggaagatcaagcctcagaaga tcgagatcaggaaggacaccctgaaaaccctgaacgacttccagaagctgctgggggaca tcaactggatccggcccaccct gggcatccccacctacgccatgagcaacctgttcagcatcctgcggggcgacagcgacct gaacagcaagagaatgctgacc cccgaggccaccaaagaaatcaaactggtggaggaaaagatccagagcgcccagatcaac aggatcgaccccctggcccc tctgcagctgctgatcttcgccaccgcccacagccctaccggcatcatcatccagaacac cgatctggtggagtggagcttcctgc cccacagcaccgtgaaaaccttcaccctgtacctggaccagatcgccaccctgatcggcc agacccggctgcggatcatcaag ctgtgcggcaacgaccccgacaagatcgtggtgcccctgaccaaagaacaggtgcgccag gccttcatcaacagcggcgcct ggcagatcgggctggccaatttcgtgggcatcatcgataaccactaccccaagaccaaga tcttccagttcctgaagctgaccac ctggatcctgcccaagatcacacggcgggagcctctggaaaacgccctgaccgtgttcac cgacggcagcagcaacggcaa agccgcctataccggccccaaagaacgggtgatcaagaccccctaccagtccgcccagcg ggccgaactggtggccgtgatc accgtgctgcaggacttcgaccagcccatcaacatcatcagcgacagcgcctacgtggtg caggccacccgggacgtggaga ccgccctgatcaagtacagcatggacgaccagctgaaccagctgttcaatctgctgcagc agaccgtgcggaagcggaacttc cccttctacatcacccacatccgggcccacaccaacctgccaggccctctgaccaaggcc aatgagcaggccgacctgctggt gtccagcgccctgattaaggcccaggaactgcacgccctgacacacgtgaatgccgccgg actgaagaacaagttcgacgtg acctggaagcaggccaaggacatcgtgcagcactgcacccagtgccaggtgctgcacctg cccacccaggaagccggcgtg aaccccaggggcctgtgccccaacgccctgtggcagatggacgtgacccacgtgcccagc ttcggcagactgagctacgtgca cgtgaccgtggacacctacagccacttcatctgggccacctgccagaccggcgagagcac cagccacgtgaagaaacacctg ctgtcctgcttcgccgtgatgggcgtgcccgagaagatcaagaccgacaacggccctggc tactgcagcaaggccttccagaa gttcctgagccagtggaagatctcccacaccacaggaattccttacaacagccagggcca ggccatcgtggagcggaccaac cggacactgaaaacacagctggtgaagcagaaagaggggggcgactccaaagagtgcacc accccccagatgcagctga acctggccctgtacaccctgaactttctgaacatctaccggaaccagaccaccacctccg ccgagcagcacctgaccggcaag aagaacagcccccacgagggcaagctgatttggtggaaggacaacaagaataagacctgg gagatcggcaaggtgatcac ^c tggggg ^a g ^a ggttttg ^c ttgtgttt ^cacca gg ^a g ^aaaa t ^ca g ^c tt ^cc tgtttgg ^a t ^acccac t ^a g ^aca tttg ^aa gtt ^c t ^aca atg ^aac ccatcggagatgcaaagaaaagcacctccgcggagacggagacaccgcaatcgagcaccg ttgactcacaagatgaacaa aatggtgacgtcagaagaacagatgaagttgccatccaccaagaaggcagagccgccgac ttgggcacaactaaagaagct gacgcagttagctacaaaatatctagagaacacaaaggtgacacaaaccccagagagtat gctgcttgcagccttgatgattgt atcaatggtggtaagtctccctatgcctgcaggagcagctgcagctaa

SEQ ID NO: 17 H. sapiens DNA

>HERV-T whole genomic sequence Gag-Pol-Env TGCCT AACCTT GTTTTT ACT CT AACT CATT ACTTT GAATTTT GTCCTGCTT GTCT CTTT AAT

CACCTATCCTTGCTTCTCATGTAAATAAGACTCTCTGTAGCTGGGAAGGCCAGACAA ACT

CCAACT GACCCCTT AATTT ACAAG ACACT AAGGGCTCCTTTCCCAACCCCCTTTT GT AAG

GAGTTGGCCTGGGT AAACAGATCCTCAGCATTTCAAAGGAGTCCAATT AACT GAT AAGG

TACT AACACCAACAAT GTAT GAAGTTCCCAGG ATTTTT CT C AAAG AGAT AACAAC AT AAA

ACCTT G AGTT CAT GT CTTCT AT AGACT CT AT AT CT AATT AT AAT GAAAG ATTT AG AACCTT

GCACCT GGT ACCTTTGCT CTT CTT GT AACCATTT GT CTTTT AAGTGGTTT AT CTCTCTGTA

ACCATTTT GCTT CTTTT GATT CTT GCAT GTTTTT ACTT CTGT AGAATT ATTGCATTT G AGT C

CCCCTCCCCTTCCTAAACCTAGGTATAAAAGTTAATCAAGCCCCTTCCTCGGGGCCG AG

AGAATTTTCAGCATTAGCCATCTCTTTGGCCGCCAGCTTAATAAAGGACTCTTAATT CGT

CTCAAAGT GTGGCAT ATTTTTT AACTCGCTT GGAT ACAACAT AATGGAGGTCCCAGT GAG

AAATTAACTCCACTGGGTGAGAGCCGGTCTCACTCTGGGCTCCCCCGGAAGGACGGC T

GGCTTGGATGGGGGGCGCCACCT GAGGAAAT AATTTTT AAGGTCCCAGAAGAGT AACT

GCCTTCCGGAGGAGAGCGGATCGACCACCGTGTCATTGCCCTAAAATTCAACATCTG A

GTCCTCAGCTTCTGACCCCGGGGTCAGGTAAGTCAGATTTGACTTCGTTTCTGGTAA GA

GGGGAGTGGCCCTGATGAGGGCGTCCCTCTTTTGACTCAGCCTGTTACTCTAGGACA C

TAGTGGGTTGAGCCTTGGTTTTCTGGTAGGTGCTTTTGTATCTTGGTTTGGGTAGGA AG

TGGTCCTGACAAGGACCCTCCACTGACTTAGCTCAGGGCCCAGGAGGCGGGAGCTAA G

CCTTGGTTTCCGGAAGACCGGACTCTCGATCTCTCTCTCTCTTTCTCTCTTGTCTAT CTT

ACATCCTT CT GTT GTT CAGGTTT CTTGG ACAAT CT CT GGG AAAGAAAAGG AAG AAAAAAA

GAGAAAAAAATT GTT AT AAACTCT GT GT AAATGGT GT GT GACT GT GGGAGGACAAGGGG

TTGCATTT GTCTTCCAGTTT GT AGCTCT ATGGT GAAAGCT ACAGAGTTCAAGTGGGCCCT

CACCTGCGGTTCCGTGGCGACCTCCTAAGGCTTAAGGCAGCACCGGGCATAGCTCGA T

CT GAGCCAGGGGTTT AT ACCAGCCT GTCGATGCT AAGAGGAGCCCAAGTCCCCTCT GG

GGGATCAGCCAGGCGGGCATCTGAATGACAGCATCACGGGAACTCCTTCCCTTGTCT G

T CT AAT AAAG AAGGT AAAAAAGGGAAAACT GT CAT AATT GTTT AC ATGCCCT AGGGTCAA

TT GTTT GTTTT AT GTTT ATT GTTTTTTT CAGT GTCT ATT GTCTT GTTT AAT AGTT GTCAAGG

TGTTAT AT GTCAAGACATCG AT ATT GCCCAAG ACGTCT AGGT AAAAACTT CTT CAAGG AC

CTTAGTGCTGATTTTTTGTCACAAGAGGTTAAATTTCTCATCAATCATTTAGGCTGG CCA

CCACAGTCCT GTCTTTT CTGCCAG AAAC AAGT AAGGTGTT GTT ACGG AAAAG AGT GT GA

AAAACATT CACCT GATCGG AATTT CTGGC ACCAT G AAGGTTGCAGGT ATTT AG ATT GTCA

TACCCCACGTCCAAGTGATTAGACCTCCTCTAAACTAAACCAGTGGTGGATTCAAAA CA

GCCACCCTGCAGACCTCCTTGCTCACCTCTTTTGTCATTCTGTAACTTTTCCTGTGC CCT

T AAAT AAAACACT GTGT AAAG AAACCT ACG ACCGT AATGCTTT ACTTCGTTT AG ACTCCT

ACTCTGTTCCCCTGTGGCTACGCTCCCACCTTAAAAATGATCCGAGTGGTCCTTTTC CC

CCTCATCCCTGCCCCCTACCCCACACATCTCGTTTTCCAGTGTGACAGCAAGTTCAG CA

T CTCCAAG ACTT GGCTCTGCT CT CACTCCTT AAACCCTT AAAAG AAAAAGCT GAATTT GA

ACT ATTTGCCTTT GAATCGTGGAGACACCAAAAAT ATCT AGGAT ACAGGTCT AGAGGAA

GAAGAAGAGGGAGAACGCCTAGATCCAACCGACCCAGGAGACCTCAGGCTGACCCCT A

ATCCCCCTCCCT C AAT CT AAAAGCT AC AG AAAT GT AGC AAGT AGT ATT AGCT GTT GTAGT

TTTTCTGTTCTTCCTGGTCATGTTAATTCTGTTTTTCCGACACTCCAGCCCCCCAGG GAA

AGAATTTCTCTGCCCGTGTTGGATCAACACTTCCTCCCAGCCCTATAAAGGTTGGAG CC

CT CTCCAAGGT AT GCTGCAGAATTTTT CT CTCGGTTT CT C AG AGG ATT ATGGAGTCCGC

CTTAAAAAAGGCAAGCTCCAGACACTCTGCGAAGTAGAATGGCCAAAGTTTGGAGTC AG

GTGGCCCCCTGAAGGGTCATTGAACCTTACAATTGTTCAAGCTGTGTGGCGGGTTGT TA

CTGAAACTCCCAGCCACCCTGATCAGTTTCCCTACATTGATCAATGGCTAAGTTTGG TCA

GGAGCCCTCCTCCATGGCTCCGTTCATGCGCCATTCATAATTCTACCTCCAAGGTCC TC

CTGAGCCAGACCGCGTTTTCGCCTCGACCCTCAGCCGGTTCAGCTCCCCCTGTACTG C

CTCCCTCTGAAGAAGAGGAGAGTCTCCCTCACCCAGTCCCACCGCCTTACAACCAGC C

TGCTCCCTTAAAGTCATCCCATGTCTCCTCGACGACGTCCCCTGTAGGCTCGCCACC CA

TTGCCT CT CAATCGT G ACCGTGGCAGGAAGAAGT AGCCCCTCTACTACCACT GAG AG A

GGCACAAGTCCCTCCAGGTGATGAGCGCTCAGCCCCCTTCTTAGTTTATGTCCCTTT TT

CT ACTT CT G ACTT GTAT AATT AG AAAACCC AT AATCCTCCCTT CT CT G AAAAGCCCCAGG

CTTT G ACCTCACT GAT GG AGTCCGT ACTCCGGACT CACCGGCCCACCT AGGAT GACT G

CCAACAGCTCCTTTTAACCCTTTTCACCTCTGAAGAGAGGGAACGTATCCGAAGAGA GG CCAGAAAGT ACTTCCTT ACATCAGCCGGT AGACCAGAGGAGGAAGCT AGAGACCTCCTT GAGGAGGTCTTTCCCTCTACCCGGCCTAATTGGGACCCAAATTCCTCAAGTGGAAAGAG AGCTTTAGACGATTTTCACCGGTATCTCCTCGCGGGTATTAAAGGAGCCGCTCAGAAAC CCAT AAACTT GTCT AAGACAACT GAAGTT GTCCAGGGGCCT GAT GAGTCACCAGGAGCG TTTTTAGAACGCCTCCAGGAGGCTTATCGGATTTACACCCCTTTTGACCCGGCAGCTCC CGAAAATAGCCGTGCTCTTAATTTGGCATTTGTGGCTCAGGCAGCCCCGGATATTAAAA G AAAACTCCAAAAACTGG AAGGATTTGCT GG AAT G AAT AT CAGTCAGCTTTT AG AAAT AG CCCAAAAAGTTTTTGACAATCGAGAGTTTGAAAAACAAAAACAAGCAACACAGGCAGCT G AAAAGGCCGCT GAT AAAGCATT CAAAAGACAAACAAAAAT CTTGGT AACAGCT ATCCAA GAGGGCAGAAAGGAAAGGCCCCCATTCCAGAAAAATGGCCAAGGAACCTCGGGTTCCC ACCAGAAAAGT AAAAGAGGT GAACAGGCCCCTCT AGGAAAAGACCAAT GTGCTT ATTGC AAGCAGACTGGGCACTGGAAAAAGGAGTGCCCACTACTGCCAAAAGAAAAATCAGAAAA GAAAAAGGTCCTCACCCTCCCCGCAACAGAGGAGTCTGATGATTGATGGGGCCAGGGC TCCCTCTCTCTTGGCCCCCAGGAGCCCATGGTGACTGCTACAGTGGGGGGCCAGCCTG T ACGCTTCCT AAT AGACACCGGGGCAGAACACTCAGT ACT GCAGACACCCTTGGGCAG TGTCTCTAATAAAAAAGTGGCTGTACAAGTAGGGGCAAACTGGAGCCAGAAAAGAGTAA CACACTCATTT CTT CAT AAGTT ACAGGCCT CT AT CTCCTT CTCAGCCCAGCAGGCT C ACC T CACACT AGG AAAT ACAACGCCCCCCACT GCCCAACTCCT GCTAACT ACCCCT CTGTCA G AAG AAT ACCTTCT GGTTT CACCAT C ACAACCACCGG AG AAT AAT ACT AAT ACTCTCCTG TTGGACCTACAGACACTCTTTCCCCGAGTTTGGGCCGAGTCAAACCCCCCAGGACTGG CAAAGCACCATCTGCCAGT AGTT GT AGAACTCCT GGCCACTGCCCTGCCAGTCCAGGT A AAACAATATCCTATGAGTCAGCAGGCTAGAGAGGGGATCAATCCCCATATTCAGTGACT GTT ACAAGCTGGCAT ACT CACACCAT GTCAGTCCGCCT GG AAT ACTCCATTTTT GCCGG TCCAGAAACCTGGAACAAAT GATT ACCAGCCAGT ACAGGACTT GAGGGAAGTT AACAAG TGGACAGTTACTGTCCATCCAACTGTCCCTAACCCTTATACTTTACTCAGCCTGCTCCCA CCAG AACAT ACAGT AT ACACT GTCCTT G ACTT AAAGG AT GCTTT CTTT GCT ATTCCT CT G GCCCCCAAAAGCCAACCT ATCTTTGCTTTT GAATGGACAGATCCTGGCTCAGGAGACAC CACCCAACTGACTTGGACTCAGTTACCTCACCCTTTTTGGGGAAGCCCTCCAACAAGAT CTT AT ACC ATTCCG AGCCCT AACTGT ACTCTT CTCCAGT ATGT AG AT G ACCTTTT ATT AG CT ACT GAAACT ACT GACAGCTGCCT GCAACAT ACT AGGGACCT ACTTT ACCTCCTTCAG GAACTCGGGTATCGGGTCTCAGCCAAGAAGGCCCAGCTTTGTCTTCCCAGAGTGTCCT ACCTGGGGTACGAGATAAACAAAGGAAAAAGGGCACTCACCAGTGCCCGGAAGGAAGC CATCCTGCGAATCCCCACTCCCACCACCAAGAGACAGGTACATGAATTCCTGGGGGCC AT GGGAT ACT GTCATCT ATGGAT ATT GGGGTT CGCAGAGATT GCAAAGCCCCT GT AT AC TGCT ACAGGAGGGAATGGCCCACT AATTT GGACT GACACAGAAGAACAGGCTTTTCAAA ATCTGAAAAAGGCATTAACTGAAGCCCCTGCTTTAGCCCTCCCAAATATCTCAAAGCCAT TTCACCT GTTT GTCCAT GAAAGCCAGGGAGTTGCT AAAGGGGT GCTT ACTCAGACTTT A AGACCCTGGAGACGCCCAGTGGCCTATTTATCTAAGAGGCTGGATCCTGTGGCCTCTG GATGGCCAAGTT GTCT GCGAGCCAT AGCGGCT ACAGCAAGCCT AGTCCAAGAAGCT GA T AAGTT AACT CT AGGCCAAAATTT AACCCTT ACAGCTCCT CATGCCGT AG AG ACTTT ACT ACGAAGTGCTTCTGGCAAATGGATGTCAAATGCTCGCATCTTGCAGTATCAGAGTTTACT GTTAGATCAGCCTCGTTTGACTTTCTCTCCCACAAGGTGTTTAAATCCAGCTACACTACT TCCTGACCCAGACTCCACTATTCCTGTCCATGACTGTCAAGAACTGTTAGAAACTATCGA AACTGGCCGACCT GATCTTCAAGAT GTGCCCCT AGAAAAGGCGGATGCCGCCGT GTTC ACAGACAGT AGCAGCTTCCTCAAGCAGGAAGT AT GAAAAGCCAGTGCAGCT GTT ACCAC CTCAGCACAAAAGGCTGAATTGATCGCCCTCACTCAGGCTCTCCGATGGGGTAAGGATA AACGT ATT AACATTT ACACT GACAGCAGGT ACGCCTTTGCT ACT GTGCAT GT ACATGGAG CCATCTACCAAGAGCGAGGGCTACTCACCTCAGCAGGAAAGACTATCAAAAACAAAGAA GAAATTTT AGCCCTGCTT GAAGCT GTTTGGCTCCCTCAGCAGGTGGCT GT AATCCACT G CAAAGGACATCAAAAAGAAAACACGGCCGTTGCCCGTGGTAACCAAAAAGCTGATTCAG CAGCTCAGGAAGTGGCACGGTCTTCAGTTACGCCCATAAACTTGCTGCCCACAGTCTCC TTTCCACAGCCAG AT CTGCCT G ACAATCCCGT AT ACT CAACAGAAGAAAAAAAACT GGC TT CAGAT CT CAGAGCCAAT AAAAAT CAGG AAGGTT GGTGGATT CTTCCT G ACT CT AGAAT CTT CAT ACCCCG AGCT CTTGG AG AAACTTT AAT CAGT CACCT ACATT CT ACC ACCCATTT AAG AAG AGCAAAGCT ACCT CAGCTCCTCCGGAGCCATTTT AAGATCCCCCAT CTT CAAA GCCTAACAGATCAAGCAGCTCTCCAGTGCACAACCTGCGCCCAGGTAAATGCCAAACAA GGTCCTAAACCCAGCCCAGGCCACCGTCTCTGAGAAAACTCGCCAGGAGAAAAGTGGG AAATT GACTTT ACAGAAGT AAAACCACACCGGGCT GAGT ACAAAT ACCTTCT AGT ACT AG T AGACACCTTCTCCGGATGGACT GAGGCATTTGCT ACCAAAAACGAAACTGCCAACACA GT AGTT AAGTTTTT ACTCAAT GAAATCATCCCTCAACATGGGCTGCCTGCTGCCAT AGGG TCTGATAATGGACCAGCCTTCACCTCGTCCATAGCTCAGTCAGTCAGTAAGGCATTAAA CATTCAATGGAAGCTCCATTGTGCCTATCGACCCCAGAGCTCTGGGCAGGTAGAACGC AT GAACCACACCCT AAAAAACACTCTT ACAAAATT AAT CTT AG AAACCGGT G AAAATT GG GT AAGTCTCCTTCCTTT AGCCCT ACTT AGAGT AAGGT GCACCCCTT ACCAGGCT AGGTT CTCACCTTTTGAAATCATGTATAGGAGGGCGCCGCCTATCTTGCCTAAGCTAAGAGATG CCCATTT AGCAG AAAT AT CACAAGCT AATTT ATT ACAGT ACCTACAGT CTCTCCAACAGG T ACAAG AT AT CATCCT GCC ACTT GTTCG AGG AGCCCATCCCAATCCAATTCCT G ACC AG ACGGGGTCCTGCCATTCGTTCCAGCCAGGAGACCTAGTGTTTGTTAAAAAGTTCCAGAA AGAAGGACTCACTCCTGCTTAGAAAAGACCTCACACCGTCATCCTCACGACGCCAACGG CTCTGAAAGTGGATGGCATTCCTGCTTGGATTCATCACTCCCGCATCAAAAAGGCCAAC AGAGCCCAGCT AGAAACATGGGTCCCCAAGCCT AGGTCAGGCCCCTT AAAACT GCACC T AAGTCAGGT G AAGCCATT AGATT AATT CTTTTT ATTT ACCTCT CTT GTTT GTTTTTGCCT GTTATGTCCTCTGTGCCTTCCTACTCCTTTCTCCTCACCTCTTTCACAACAGGACGTGTA TTTGCAAACACCACTT AGAAGGCCAGT ACCTCCAAGGAAGTCTCCTTTGCAGTT GATTT A TGTGTACT GTTCCCAAAGCCAGCCCAT ACCCACGAAAAGCAACACAAT CT GCCAGTCCC AGGAGCAGGAAGT GTCGACCTTGCAGCAGGATTT AGACACTCCAGGAGCCAAACT AGA TGT GG AAGCTCCAAAGGT GCAG AAAAAGG ACTCCAAAAT GTT G ACTTTT ACCT CTGTCC TGGAAAT CACCCT G ACGCT AGCT GTCGAG AT ACTT AT CAGTTTTT CTGCCCT G ATTGG AC ATGTGT AACTTT AGCCACCT ACT CTGG AAG AT CAACCAG AT CTT CAACT CTTTCCAT AAG TCGTGCTT CT CATCCT AAATT ATGTACT AG AAAAAATT GT AATCCT CTT ACT AT AACT GTC CAT GACCCT AATTCAGCTCAAT GGT ATT ATGGCAT GTCATGGGGATT AA GACTTT AT ATC CCAGG ATTT GAT GTT GG AACT AT GTT CACCATCCAAAAGAAAATCCTGGTCTCATGG AG CCCACCCAAGCCAATCAGGCCTTT AACT GATCT AGGT GACCCT AT GTTCCAGAAACACC CT G ACAAAGTT GATTT AACT GTTCCTCCACCATTCCT AGTTCCT AAACCCCAGCTGCAAA G ACAACACCTCCAACCCAGCCT GAT GTCCAT ACTAGGTGGGGT ACAT CACCTCCTT AAT CTCACCCAGCCT AAACT AGCCCAAGATT GTTGGCT AT GTCT AAAAGCAAAACCCCCAT AT T AT GT AGGATT AGGAGT AGAAGCCACACTT AAAAGTGGCCCTTT ATCCT GTCAT GCACG ACCCCAT GCCCTCACATT AGG AG AT GT GTCTGGAAATGCTT CTT GTCT AATT AGT ACTGG ATATAACTTATCTGCTTCTCCCTTTCAGGCTACCTGTAATCAGTCTCTGCTTACTTCCTT A AGCACCTCAGTCTCCTACCAGGCACCTAACAATACCTGGTTGGCCTGCACTTCAGGTCT CACTCGCTGCATCAATGGGACTGAACCAGGACCTCTCCTGTGTGTGTTGGTTCATGTAC TCCCCCAGGTCTACGTGTACAGTGGGCCAGAAGGACAACTTCTCATTGCTCCCCCTGAA TT ACATCCCAGGCT ACACAGAGCT GCCCCACT ACTGGTTCCTCTTTT AGCCGGTCTT AG CATAGCTGGATCAGCAGCCATTGGCACGGCTGCCCTGGTTCAGGGAGAAACTGGACTA ATGTCCCTGTCT CAACAAGT AG ATGCT GATTT AAGCAAT CTCCAGTCAGCCAT AAAT AT A CT ACAT ACCCAGGT AGAGTCT CT AGCT G AAGT AGTT CTT CAAAACCGCCG AGGCTT AGA TCTGCTATTTCTCTCCCAAGGAGGGTTATGCGCAGCTCTAGGAGAAAGTTGTTGCTTCT AT GCCAAT CAGTCTGGAGTCAT AAAAGAT AC ACTCCAAAAAGTT CAAG AAAAT CT AG AT A GGCGCCAACAAGAACAAGAAAAT AACATCCCCTGGT ATCAAAGCAT GTTCAACT GGAAC CCATGGCTAACTACTCTAATCACTGGGTTAGCCGGACCCCTCCCCATCCTACTATTAAG TCT AATTTTTGGGCCTT GT AT ATT AAATTGGTTTCTT AATTTT GT AAAACAACGCAT AGCTT CT GTCAAACTT ATGTAT CTT AAAACT CAAT AT AACCCCCTT GTT AT AACT G AGG AAT CAAC GATTT G ATTCCCCT AAAACACAAGTGGGG AAAT G AAAT GCCT AACCTT GTTTTT ACT CT A ACT CATT ACTTT G AATTTT GTCCT GCTT GTCT CTTT AAT CACCT ATCCTTGCTT CT CAT GT AAAT AAG ACT CTCTGTAGCT G AGAAGGTCGGACCAACTCCAATT GACCCCTT AATTT AT A AGACACT AAGGGCTCCTT ACCCAACCCCCTTTT GT AAGGAGTT GGCCTGGGT AAACAGA TCCT CAGC ATTT CAAAAG AGCCCAAGT AACT GACAAGGT ACT AACACCAACAAT GTAT GA AGTTCCCAGG ATTTTT CT C AAAG AGAT G ACAAC AT AAAACCT GG AGTT CAT GTCTGGCAT AGACCCT AT AT CT AATT AT AAT G AAA GATTT AGAACCTT GCACCTACT ACCATTGCT CTT C TTGT AACCATTT GT CTTTT AAGTT GTTT ATTT CTCTGT AACCAGTTTGCTT CTTTT GATT CT TGCAT GTTTTT ACTT CTGT AG AATT ATTGCATTT G AGTCCCCCTCCTCTTCCT AAACCT AG GTATAAAAGTTAATCAAGCCCCTTCCTCGGGGCCGAGAGAATTTTGAGCATTAGCCATC T CTTTGGCGCCCAGCTT AAT AAAGG ACT CTT AATT CAT CT CAAAGT GTGGTGT ATTTTTT A ACTTGCTTGGGTACAACA

SEQ ID NO: 18 H. sapiens DNA

>HERV-W whole genomic DNA Gag-Pol-Env

ACT GAGAGACAGGACT AGCTGGATTTCCT AGGCCGACT AAGAATCCCT AAGCCT AGCT G GGAAGGT GACCACGTCCACCTTT AAACACGGGGCTTGCAACTT AGCTCACACCT GACCA ATCAGAGAGCTCACTAAAATGCTAATTAGGCAAAGACAGGAGGTAAAGAAATAGCCAAT CATCT ATTGCCT GAGAGCACAGCAGGAGGGACAACAATCGGGAT AT AAACCCAGGCATT CGAGCTGGCAACAGCAGCCCCCCTTTGGGTCCCTTCCCTTT GT ATGGGAGCT GTTTTCA TGCTATTTCACTCTATTAAATCTTGCAACTGCACTCTTCTGGTCCATGTTTCTTACGGCT C GAGCT GAGCTTTTGCTCACCGTCCACCACTGCT GTTT GCCACCACCGCAGACCTGCCG CTGACTCCCATCCCTCTGGATCCTGCAGGGTGTCCGCTGTGCTCCTGATCCAGCGAGG CGCCCATT GCCGCTCCCAATT GGGCT AAAGGCTTGCCATT GTTCCT GCACGGCT AAGT G CCTGGGTTT GTT CT AATT GAGCT G AACACT AGT CACTGGGTTCCATGGTT CT CTTCT GT G ACCCACGGCTTCT AAT AGAACT AT AACACTT ACCACATGGCCCAAGATTCCATTCCTTGG AATCCGTGAGGCCAAGAACTCCAGGTCAGAGAATACGAGGCTTGCCACCATCTTGGAA GCGGCCTGCT ACCATCTTGGAAGT GGTTCACCACCATCTTGGGAGCTCT GT GAGCAAG GACCCCCCGGTAACATTTTGGCAACCACGAACGGACATCCAAAGCGGTGAGTAATATTG GACCACTTTCACTTGCTATTCTGTCCTATCCTTCCTTAGAATTGGAGGAAAATACCGGGC ACCT GTCGGCCAGTT AAAAACGATT AGCGT GGCCACCGGACTT AAGACTCAGGT GT GA GGCT ATCTGGGGAAGGGCTTTCT AACAACCCCCAACCCTTCT GGGTT GGGAACGTT GG TCTGCCTCGAAGCCAGCTTCCACTTTCAATTTTCTTGGGGAAGCCGAGGGCCGACTAGA GGCAGAAAGCTGTCGTCCCGAACTCCCGGCAGTAGCCGGTTGAGATCATGGCGCAGC CAGAAGTCTCTACTCAACAGTCGCCCATGCATGCACCCCTACCTTTCCTTCTGACCCAT ACCTCCTGGGTCCCAACCACAACTTTCTTCAAAGTGTAGCCCCAAAATTCTCCTTACCTC TGAATATACTTCCTCTGATCCCTGCCTCCTAGGTACTAATGGTTCAGACTTCCATTTCCT CTAGCAAGTTGTATCTCCAAAGGGATCTAAGGAAGCTCTACGCTGCGTCCTTAGGCACC TAGGCTATGAACCCAGGGAGTCTTATCCCTGGTGTCCCTCCCAATTTAGGCATACAGCT CTCGACATGGGCAGTT AT GT AGGACCCACTCCCCACCACCCTTGCCAGGGCCCCAAGT TT GT AAATGGCT AAGAGAAAAGAGAGACAGAGGAGAGAGAGAGAAATGGAGGAGAAAG AGAGAGAGACAGAGAGGAGAGAGAGACAGAGAGAGAGACAGAGAGAGAGAGAGAGAC AAAGAGGAGAGAGAGAGAGTCAAAGAGAGAAAGAAAGAGAAAGAAATAGTAAAAAACA GTGTGCCCT ATTCCTTT AAAAGCCAGGGT AAATTT AAAACCT AT AATT GAT AATT GAAGG T CTT CTCCAT G ACCCT AT AACACTCCAAT ACCACCTT GTGGTCAGT GT AAAC AAGAGCAT AGCCCGAAAACACT G AGACCACT GACAACCCGT AGCCTCCCTAT CAAAAATCCTT AACC CAGT AACCCACAGATGGACCAAATGCATTCAATCGGT AGCGGCAACTGCTTTGCT AACA G AAAAAAGT AGAAAAGT AACTTTT AGAGGAAACCT CATT GT G AGC ACACCT CACCAGTT C AGAATT ATT CT AAGT AAAAAAAGCAAAAAGGT AGCTT ACT AACT CAAAAAT CTT AAAGT AT GGGGCT ATTCT GTT AGAAAAAGGT AAT GT AACACCAACCACT GAT AATTCCCTT AACCCA GCAGATTTCCT AACAGGGGATTT AAATCTT AATT ACCAT ACAAAGGTCCGACCAGACCT A GGAGGAACTCCCTTCAGGACAGGACGATAGATGGTTCCTCCCAGGTGATTGAGGAAAA AAACCACAAT GGGT ATTCAGT AATT GAT ACGGAGACTCTT GTGGAAGCAGAGTT AGAAA AATTGCCT AAT AACTGGTCTCCTCAAACGT GCGAGCT GTTTGCACTCAGCCAAGCCTT A AAGT ACTT ACAGAAT CAAAAG ACT AT CT CAATCCT GACT CAAAAGGTT ACCT ACACCCT C TCT GAAAT GAATTTGCAT AAGAACT GTT GTTT AT GGGAATGCATCTT GAT GGGGCAGCT G GGTT GTT AT AAAAT ACTCAGGAACCCAGCCCAGCTCT AGGACTCACCCCT GAGCACAAA GGCAAT GTTGGGCACGCT GGT AAAGGACCACT AGAATCCAGCAGCCCAGACCCCTTTC TTT GT GGTCAAGAAAGGCGGGAAAACAGGT GCAGGACTGCT ACATCGGT AAGCAT AACT AATCCGAT AAACAGAGGTCCAT GGGT GGTT ACGCACCCTGGAAAGGAACTCACCCCT G AGCACAAAGGCAATGTTGGGCACGCTGGTAAAGGACCACTAGAATCCAGCAGCCCGGA CCCCTTTCTTTGTGGTCAAGAAAGGCAGGAAAACAGGTGCAGGACTGCAACATCAGTGA GCAT AACT AATCCGAT AAGCAGAGGTCCATGGGTGGT GACGCACCCT GGAAAGGAAT A AGCATTAGGACCATAGAGGACACTCCAGGACTAAAGCTCATCGGAAAATGACTAGGGGT GCTGGCATCCCTATGTTCTTTTTTCAGATGGGAAACGTTCCCCCCAAGGCAAAAACGCC CCT AAGAT GT ATTCTGGAGAATT GGGACCAATTT GACCCCTCAGACGCT AAGAAAGAAA T GACTT AT ATTCTTCTGCAGT ACCGCCT GGCGGGAAGT AT AAATT AT AACACCATCTT AC AGCT AGACCTCTTTT GT AGAAAAGAAGGCAAATGGAGT GAAGTGCCAT AT GT ACAAACTT T CTTTT CATT AAG AG ACAACTCGCAATT AT GT AAAAAGT GT G ATTT ATGCCCT ACAGGAA GCCCTCAGAGTCTACCTCCCTACCCCAGCATCCCCCCGACTCCTTCCCCAACTAATAAG GACCCCCCTTCAACCCAAATGGTCCAAAAGGAGATAGACAAAGGGGTAAACAATGAACC AAAGAGT GCCAAT ATTCCCCGATT ATGCCCCCTCCAAGCAGTGGGAGGAGGAGAATTC GGCCCAGCCAGAGT GCAT GT ACCTTTTTCTCT CT CAG ACTT AAAGCAAATT AAAAT AG AC CTAGGT AAATT CT CAGAT AACCCT GAT GGCTAT ATT GAT GTTTT ACAAGGGTT AGG ACAA TCCTTT G ATCT GACATGG AG AGAT AT AAT GTT ACTGCT AAAT CAG ACACT AACCCCAAAT GAGAGAAGTGCCGCCATAACTGCAGCCCGAGAGTTTGGCGATCTCTGGTATCTCAGTC AGGTCAATGATAGGATGACAACAGAGGAAAGAGAACGATTCCCCACAGGCCAGCAGGC AGTTCCCAGT GT AGACCCTCACT GGGACACAGAATCAGAACATGGAGATTGGTGCCGC AGACATTT GCT AACTT GCGTGCT AGAAGGACT AAGGAAAACT AGGAAGAAGCCT AT GAA TT ATT CAAT GAT GTCCACTAT AACACAGGG AAAGG AAG AAAATCCT ACTGCCTTT CTGGA GAG ACT AAGGG AGGCATT GAGGAAGCAT ACCTCTCTGTCACCT GACT CT ATT G AAGGCC AACT AATCTT AAAGG AT AAGTTT AT CACTCAGTCAGCTGCAG ACATT AG AAAAAAACTT C AAAAGTCTGCCTT AGGCCCGGAGCAAAACTT AGAAACCCT ATT GAACTTGGCAACCTCG GTTTTTTATAATAGAGATCAGGAGGAGCAGGCGGAACGGGACAAACGGGATTAAAAAAA AGGCCACCGCTTTAGTCATGGCCCTCAGGCAAGCGGACTTTGGAGGCTCTGGAAAAGG GAAAAGCTGGGCAAATCGAATGCCTAATAGGGCTTGCTTCCAGTGCGGTCTACAAGGA CACTTT AAAAAAGATT GTCCAAGT AG AAAT AAGCCGCCCCCTCGTCCAT GCCCCTT ATGT CAAGGGAATCACTGGAAGGCCCACTGCCCCAGGGGATGAAGGTCCTCTGAGTCAGAAG CCACTAACCAGATGATCCAGCAGCAGGACTGAGGGTGCCCGGGGCAAGCGCCAGCCC AT GCCATCACCCTCACAGAGCCCCGGGT ATGCTT GACCATT GAGGGCCAGGAGGTT AA CTGTCTCCTGGACACTGGCGCGGCCTTCTCAGTCTTACTCTCCTGTCCCGGACAACTGT CCTCCAGATCTGTCACTATCCGAGGGGTCCTAGGACAGCCAGTCACTAGATACTTCTCC CAGCCACT AAGTT GT GACTGGGGAACTTT ACTCTTTTCACATGCTTTTCT AATT ATGCCT GAAAGCCCCACTCCCTT GTT AGGGAGAGACATTCT AGCAAAAGCAGGGGCCATT AT ACA CCT GAA CAT AGGAGAAGGAACACCCGTTT GTT GTCCCCTGCTT GAGGAAGGAATT AATC CT GAAGTCTGGGCAACAGAAGGACAAT ATGGACGAGCAAAGAATGCCCATCCT GTTCAA GTT AAACT AAAGGATTCCGCCTCCTTTCCCT ACCAAAGGCAGT ACCCCCTT AGACCCGA GGCCCAACAAGGACTCCAAAAGATTGTTAAGGACCTAAAAGCCCAAGGCCTAGTAAAAC CAT GCAAT AGCCCCTGCAAT ACTCCAATTTT AGGAGT ACAGAAACCCAACGGACAGT GG AGGTTAGTGCAAGATCTCAGGATTATCAATGAGGCCGTTGTCCCTCTATACCCAGCTGT ACCT AACCCTT AT ACTCT GCTTTCCCAAAT ACCAGAGGAAGCAG AGTGGTTT ACAGTCCT GGACCTT AAGG ATGCCTTTTT CTGCATCCCT GT ACATCCT G ACTCTCAATT CTT GTTT GC CTTTGAAGATCCTTCGAACCCAACGTCTCAACTCACCTGGACTGTTTTACCCCAAGGGTT CAGGGAT AGCCCCCATCT ATTT GGCCAGGCATT AGCCCAAGACTT GAGCCAGTTCTCAT ACCT GG ACACTCTT GTCCTTCGGT ACGTGG AT G ATTT ACTTTT AGCCGCCCGTT CAG AA ACCTT GTGCCATCAAGCCACCCAAGCGCTCTT AAATTTCCTCGCT ACCT GT GGCT ACAA GGTTTCCAAACCAAAGGCTCAGCTCTGCTCACAGCAGGTTAAATACTTAGGGCTAAAAT T ATCCAAAGGCACCAGGGCCCTCAGT GAGGAAT GT ATCCAGCCT AT ACTGGCTT ATCCT CATCCCAAAACCCT AAAGCAACT AAGAGGGTTCCTTGGCAT AACAGGCTTCT GCCGAAT ATGGATTCCCAGGTACGGCGAAATAGCCAGGCCATTATATACACTAATTAAGGAAACTC AGAAAGCCAAT ACCCATTT AGT AGAT GGACACCT GAAGCAGGCCCT AACCCAAGCCCCA GT GTT AAGCTTGCCAACGGGGCAAGACTTTTCTTT AT AT GTCACAGAAAAAACAGGAAT A GCTCTAGGAGTCCTTACACAGGTCCGAGGGACGAGCTTGCAACCCGTGGCATACCTGA GTAAGGAAATTGATGTAGTGGCAAAGGGTTGGCCTCATTGTTTACGGGTAGTGGCGGC AGT AGCAGTCTT AGT AT CT G AAGC AGTT AAAAT AAT ACAGGG AAGAG AT CTT ACTGTGTG GACATCTCAT GAT GT GAATGGCAT ACTCACTGCT AAAGGAGACTT GTGGCT GTCAGACA ACCATTT ACTT AAAT ATCAGGCTCT ATT ACTT GAAGGGCCAGT GCT GCGACT GCGCACTT GT GCAACT CTT AACCCAGCCAC ATTT CTTCC AG AC AAT GAAGAAAAGAT AG AACAT AACT GTCAACAAGTAATTGCTCAAACCTACGCCACTCGAGGGGACCTTTTAGAGGTTCCCTTG ACT GATCCCG ACCT CAACTT GTATACT G ATGG AAGTTCCTTT GT AG AAAAAGG ACTTCGA AAAGCGGGGT ATGCAGTGGTCAGT GAT AATGGAAT ACTT GAAAGT AATCCCCTCACTCC AGGAACT AGTGCTCAGCT GGCAGAACT AAT AGCCCTCACTCGGGCACT AGAATT AGGA GAAGGAAAAAGGGT AAAT AT AT AT ACAGACTCT AAGT ATGCTT ACCT AGTCCTCCATGCC CAT GCAGCAAT AT GGAGAGAAAGGGAATTCCT AACTTCCGAGGGAACACCT ATCAAACA TCAGGAAGCCATT AGGAGATT ATT ATT GGCT GT ACAGAAACCT AAAGAGGTGGCAGTCT TACACTGCCGGGGTCATCAGAAAGGAAAGGAAAGGGAAATAGAAGGGAACCGCCAAGC GGAT ATT GAAGCCAAAAGAGCCGCAAGGCAGGACCCTCCATT AGAAATGCTT AT AGAAG GACCCCT AGT ATGGGGT AATCCCCTCCGGGAAACCAAGCCCCAGT ACTCAGCAGAAGA AATAGAATGGGGAACCTCACGAGGACATAGTTTCCTCCCCTCAGGATGGCTAGCCACC G AAGAAGG AAAAAT ACTTTTGCCTGCAGCT AACC AAT GG AAATT ACTT AAAACCCTT CAC CAAACCTTTCACTT AGGCATT GAT AGCACCCATCAGAT GGCCAAATCATT ATTT ACTGGA CCAGGCCTTTT CAAAACT AT CAAGCAG AT AGTCAGGGCCTGT G AAGT GTGCCAAAGAAA TAATCCCCTGCCTTATCGCCAAGCTCCTTCAGGAGAACAAAGAACAGGCCATTACCCAG G AG AAG ACT GGCAACT AG ATTTT ACCCACATGCCCAAAT CT CAGGG ATTT CAGT AT CT AC T AGTCTGGGT AGAT ACTTTCACT GGTTGGGCAGAGGCCTTCCCTT GT AGGACAGAAAAG GCCCAAGAGGT AAT AAAGGCACT AATTCAT GAAAT AATTCCCAGATTCGGACTTCCCCG AGGCTT ACAGAGT GACAAT GGCCCT GCTTTCAAGGCTGCAGT AACCCAGGGAGT ATCC CAGGCGTT AGGCAT ACAAT ATCACTT ACACTGCGCCT GGAGGCCACAATCCTCAGGAAA AGTCGAGAAAATGAATGAAACACTCAAACGACATCTAAAAAAGCTAACCCAAGAAACCC ACCTCGCATGGCCTGCTCTGTTGCCTATAGCCTTACTAAGAATCCAAAACTCTCCCCAAA AAGCAGGACTT AGCCCAT ACGAAAT GCT GT AT GGACAGCCCTTCCT AACCAAT GACCTT GT GCTT G ACCG AG AG AT GGCCAACTT AGTTGCAG ACAT CACCTCCTT AGCCAAAT AT CA ACAAGTTCTT AAAACATT ACAAGGAACCT GTCCCT GAGAGGAGGGAAAGGAATT ATTCC ACCCTGGTGACATGGTATTAGTCAAGTCCCTTCCCTCTAATTCCCCATCCCTAGATACAT CCTGGGAAGGACCCTACCCAGTCATTTTATCTACCCCAACCGCGGTTAAAGTGGCTGGA GT GG AGT CTTGG AT ACAT CACACTCG AGT CAAACCCTGG AT ACTGCCAAAGG AACCCGA AAATCCAGGAGACAACGCTAGCTATTCCTGTGAACCTCTAGAGGATCTGCGCCTGCTCT TCAAGCGACAACCGT GAGGAAAGT AACT AAAATCGT AAATCCCCATGGCCCTCCCTT AT CAT ATTTTTCTCTTT ACT GTT CT CTT ACCCCCTTT CACTCT CACT GCACCCCCTCCATGCC GCT GT ACT ACCAGT AGCTCCCCTT ACCAAGAGCTTCT ATGGAGAAT GCAGCTTCCCAGA AAT ATT GATGCCCCATCGT AT AGGAGTTTTTCT AAAGGAAACCCCACTTTCACCGCCCAC ACCCAT ATGCCCCACAACTGCT AT AATTTGCAT GCATGCAAAT AGTT GTCCTGGAGGACT TGGAGCCACTGTCTGTTGGACTTACTTCACCCATACCGGTATGTCTGATGGGGGTGGAG TTCAAGATCAGGCAAGAGAAAAACACGTAAAGGAAGTAATCTCCCAACTGACCCGGGTA CAT AGCACCCCT AGCCCCT AC AAAGG ACT AG ATT CT CT CAAAACT ACAT G AAACCCTCC GT ACCCAT ACTCGCCTGGT AAGCCT ATTT AAT ACCACCCTCACTGGGCT CCAT GAGGTC TCGGCCCAAAACCCT ACT AACT GTTGGAT GTGCCTCCCCCT GCACTTCAGGCCAT ACAT TTCAATCCCT GT ACCT GAACAATGGAA CAACTT CAGCACAGAAAT AAACACCACTTCCGT TTT AGT AGGACCT CTT GTTTCCAAT CTGG AAAT AACCCAT ACCT CAAAACCT CACCT GT G T AAAATTT AGCAAT ACT AT AGACACAACCAACTCCCAATGCAT C AGGT GGGTAACTCCTC CCACACGAATAGTCTGCCTACCCTCAGGAATATTTTTTGTCTGTGGTACCTCAGCCTATC GTT GTTT G AATGGCT CTT CAGAAT CTATGTGCTTCCTCT CATT CTT AGTGCCCCCT AT GA CCAT CT ACACT G AACAAG ATTT AT ACAAT CAT GTTGTACCT AAGCCCCGCAAC AAAAG AG TACCCATTCTTCCTTTTGTTATCGGAGCAGGAGTGCTAGGTGGACTAGGTACTGGCATT GGCGGTATCACAACCTCTACTCAGTTCTACTACAAACTATCTCAAGAACTAAATGGTGAC ATGGAACGGGTCGCCGACTCCCTGGTCACCTTGCAAGATCAACTTAACTCCCTAGCAGC AGTAGTCCTTCAAAATCGAAGAGCTTTAGACTTGCTAACCGCCGAAAGAGGGGGAACCT GTTT ATTTTT AGGGGAAGAATGCT GTT ATT AT GTT AAT CAATCCGG AATCGTCACCG AGA AAGTT AAAGAAATT CAAG ATCG AAT ACAACGT AG AGCAG AGGAGCTT CAAAACACT GG A CCCTGGGGCCTCCTCAGCCAATGGATGCCCTGGATTCTCCCCTTCTTAGGACCTCTAGC AGCTAT AAT ATT GTT ACTCCTCTTT GG ACCCT GTAT CTTT AACCTCCTT GTT AAGTTT GT C TCTTCCAGAATCGAAGCTGTCAAATGGAGCCCCAGATGCAGTCCATGACTAAGATCTAC

CGCGGACCCCTGGACCGGCCTGCTAGCCCATGCTCCGATGTTAATGACATCGAAGGC A

CCCCTCCCGAGGAAATCTCAACTGCACAACCCCTACTATGCCCCAATTCAGCAGGAA GC

AGTTAGAGCGGTCATCGGCCAACCTCCCCAACAGCACTTAGGTTTTCCTGTTGAGAG GG

GGGACT GAGAGACAGGACT AGCTGGATTTCCT AGGCT GACT AAGAATCCCT AAGCCT A

GCT GGGAAGGT GACCACATCCACCTTT AAACACGGGGCTTGCAACTT AGCTCACACCT G

ACCAAT C AG AG AGCT CACT AAAATGCT AATT AGGCAAAGACAGG AGGT AAAGAAAT AGC

CAATCATCT ATT GCCT GAGAGCACAGCAGGAGGGACAAT GATCGGGAT AT AAACCCAAG

TCTTCGAGCCGGCAACGGCAACCCCCTTTGGGTCCCCTCCCTTTGTATGGGAGCTCT G

TTTT CAT GCT ATTT CACT CT ATT AAATCTT GCAACT GCACT CTT CTGGTCCAT GTTT CTT A

CGGCTTGAGCTGAGCTTTCGCTCGCCATCCACCACTGCTGTTTGCCGCCACCGCAGA C

CCGCCGCTGACTCCCATCCCTCTGGATCATGCAGGGTGTCCGCTGTGCTCCTGATCC A

GCGAGGCACCCATTGCCGCTCCCAATCGGGCTAAAGGCTTGCCATTGTTCCTGCATG G

CTAAGTGCCTGGGTTCATCCTAATTGAGCTGAACACTAGTCACTGGGTTCCATGGTT CT

CTT CTGT G ACCC ACAGCTT CT AAT AGAGCT AT AACACT CACCGCATGGCCCAAGGTTCC

ATTCCTTGAATCCATAAGGCCAAGAACCCCAGGTCAGAGAACACGAGGCTTGCCACC AT

CTTGGGAGC

SEQ ID NO: 19 H. sapiens DNA

>HERV-R whole genomic sequence Gag-Pol-Env

GGCAGGAAATATAAAAGGAAAAACAAGTAAAGGGAAAACAAGTCCTTCCCTGATCAG TC T GACTCACTCCAAAGTCCTGCTGGAGCT AT GAT AACATT ATCTGCAAGGCCAGGCAGGG ACCCCAAAAGAATGGGCTCCAGGAGCAGAGATGAGAAAAACAAGTTCTCCTTATCAGTT TCCGCCTT G AAATT CTTTCCCCAT ACC ATT ATT CTTT GTTCTGCTCT CACAACT ATTTTT G T AACT ATTT CTGCAAGTTT GCAAAG ATTT CAT AAGTTCCT GTTTTT CTTT CTGT AGCACGG CAAGGTCACAAGACAT GCTT AAGT AAG AT AGGGT CAT GTT GCAAATCCT GTTGT AAAACC TGTCACGGTAT GATT AACT GTCTTT GTT CTGCTT CT GT AAGACTGCTTTCCT GTCTCACA GGTTTCATGCCAAAAACCT GACCCGCCCCT GTT GGTTGCAT GT AT AAAAGTCAAGCCCT GTCATTGTTCAGGGCTCAGCCTTTGGATGTTCATCGGCTGGGCTGGTGGTCACCTAAAT AAAATCCTCCTGTTCCACCAAGTGGTCTCTCCAGCCTCCTGATTCCCACAACATTTTGGC GAGCCAGCCAGGAGGGGAGACT ACAGGTTT ACT GTCTCCTTTGGCT GTGGGACTGGAG CCCCGGGCTGGGGGAGACCCGTGACCCAAGGCACCATTGGGAGACCTTCAACCCGGA GGGGAGATTGGCTCTCCCATGACCCGGCGCCCCTCCCTGACAGTGCATTGGAACCTAA GGGGCTACAGGACGATTCCAGGACTTCACGCTACAGGACTGCAGTAAGGTTTGGGCCC AAGGCAGGACCCGTCCCATAAGGATGGAAGGGGAGCCTGATCACCTCCTGGGGTGTAC CT AGT AATCCGACTCAGGACAT GAGAGGGGCTCGCAAAGTTGGAAGAAACCT ACACCC CAACT GACCCAGGACGT GAGAGT GGCTCACT AAGTT GGTT AAGAAAGGAAACT GGAAG TGGGGAGGT GT GT GAAT AAAT GT GAAAGAGAT GGTTCCAAAAGGAACCAACATGCT GAG T GACGT GT GTGGAGCCACAGGTCTCTT AGCAT AGACT GT ACCATCT GAGT GAAGT GT GG AACCGACCGAGACT AGTGGCAAACATCCTTTGGGGCT ACGGCAT ATGGCTT AGGGAGG TGCCCCACAACTT AT AGATT GTGGT GGTCCGGGTTCAGGACTCAT AT GAACCCTCCATT AAAT CT AAG AAGT GTCT G AAAT ACTCCT GCAAGGG ACACGGT CT AAT CAGTCT G AAAT G AAAGGAAGAGT GAGTGGGTTCTGCCAT AACTGGGAGGAAATGGGAGGGAAGTCATCAA AACCCACCCCATT AGAAT GT AT GTT AAAGAACTTT AAGAAAGGTT AT ACAGGGGATT AT G GGATCAAGTT GACCCCCCAGAGGTT GAGAACT CTCT GT GAAAT AGAATGGCCCTCTTTT AATGTTGGATGGCCGGCCGAAGGAACTATAGATAGGGAAACAATTGGCCATGTATTTAA GGTGGTGACTGGGGTCAGAGGACAGCCAGGGCATCCAGACCAATTTCCTTATATTGAC TCAT GGCT AAAT AT AGTTCAAACTCAACCTGCATGGCT GCAGCCCTGCCT GGCAGCTT A TTGCAAAACGCTCGT AGCTCGAGCCGAGCCT AAAGT GAAAGAAAAATCAGCTTCACT GT CAGCTACAGAGACAAAGGGAAAGCCACAAGAAAAACCAGTTTTGCAGGAACCACCAGA GGAGATAGAAATCCCTCCTCCCTATACCCCAATCTACCCCCCTTTACCAAGGCCGGCCC CT GAGCAGCCAGACTCAGATGGT GACACACCCCAGGCT ACACCCCAAAGGGAGAAATC TGAGCCCCCACCCCAGGAGGTCAAGGAGGAAAGTCAGGATGATCAAGCAGGCCGCCTT CGACCT GGCCACACCAGAGT GT GGCAGATGCCCCTCCAGGAAACACGGGGACCCATCT ATTATGATGAACAGGGCCAGGTTCAAGGGGGGGCAACCGACTTTTATTTACCAGCCTTT TTCAACCACTGATCTCCTACTGGAAACACCATACTCCCTACTCCCTCCTACATGGAGAAG CCCCAGGCCCTCATAGATCTGATGCAGTCCATCTTCCAGACACACAATCCAACCTGGCC AGATTGCAAACAGCTCCTCCT GACACT GTTT AACACCGAGGAGTGCCGAAGGGT GACC CAGGCAGCCCTCCACT GGCT AGAAGCCAAT GCACCAGAAGGCACACTT AAT GTCCAGG CAT ATGCTCAGGGCCAGTTCCCAGAAGCAGACCCACACTGGGACCCAAAT GATGCAAC CCAATT ACAGCACCTGCAGAGGT ACCGAGAGGCACTCCTGCAAGGGCT AAAGGAAGGT GGGAAAAAGGCAGTCAACATGGGGAAAATCTTGGAAGTGCTGCAGGGAACTGATGAAA GCCCT AGCCAGTTTT AT GAGAGACTCT GT GAGGCATTCCAGCTTT ACACTCCGTTT GAC CCTGAGGCTACTGAAAATCAGTGCATGGTGAACACAGCATTTGTAGGACAAGCCCAGG GGGACATCAGGCGAAAGCTGCAAAAGCTAGAGGGTTTCGCAGGCATGAATGCCACCCA GCTTTTAGAAGTGGCCACCAAGGTGTATGTTAACCGTGACCAGGAGGCAAAGAGAGGC T GATCAGAGACT GGAAAAAGGCCGATCT GCT AGT GGCAGCCCTCACAGAAAGGGAAAC TAGCATCGCGAGTGGGTGTGGACATAGCCATGGACATGGAGGGGTTCAGGCCAGGCA GAGACCT GAAAGTCAACCAAGACT AT GT AGGAATCAAT GTGCACAATGCAAAAAGAAGG GACACTGGAAAAAT GAAT GTCCAGAGGGCAAT GAAGAAAAT GACAGAGACT AT AAAACT GGAAAACT GCCAGCCAAGGGCT ATT GT GTCCCAAGGGAGCCAGAT ACCAACCT GATCA GGCT GGCAGGGACT GAAGAAT AT GAAGACT AGGCCAGACTGGGCTCCTTCTCCTT AGG CCCCCAGGAGCCCAT GGTCACATT AGAAGT AGGGGGCCAACT AATGGACTTT ATGGTA GACACTGGGGCT GAACACTCGGT AGT GACCCAGCCCAT AGGGCCACT ATCCAAAAACC ATACAACTATTGTTGGGGCTACAGGGGTCCCAGAGAAGAGGCCATTTTGTCAGCCAAG GAGGTGTGTCATAGGAGGACGAGAAGTCCAACATGAATTCCTGTACCTCCCAAATTGTC CAGTTCCCTTGCTGGGAAGAGACCTACTCCAAAAACTGCAAGCACAGATTGCTTTTGGG CCACAAGGAGAT AT GACTTT AAACCT AACTCACCCAAAGGCCATGGT GTT AACCCTT AC CATCCCACAGGCT GAGGAAT GGAGACT AT ACAT GAAGT ACAGGCACCAATGCAGCCTT GT ACGCAGGAGGAAGAGAAATT ATT ATTT AGGCCAATT GAT AAAATTCCT GGAGT AT GG GCTGAAGACAACCCACCTGGGCTGGCTGTAAATCAGGCACTGGTAGTAGAATTAAAACC AGGAGCAACTCCAGTTCAGGTTCGTCAGTACCCACTTTCCCAAGAGGATATATGGGGCA TTT AT AAACATTT AAAGT GGCTCTGT G AACATGG AAT CAT AGTCCAATGCCAGT CACCCT GGAACACTCCACTTTTGCTGGT ACAAAAACCATTGCCAGGACCAGGATCT GAT GAGT AT AGACCGGTGCAGGACTT GCATGCT GT AAACCAAGCCACGGT GACCATCCATCCAGT AG T ACCAAACCT GT AT ACTTT AATGGGACTT ATTCCAGCAAGTGCT ACCT GGTTT ACAGTCC TGGACTTAAAGGATGCTTTCTTCTGTCTCTACCTGGCACCAATTAGTCAGCCCATCTTTG CATTTCAATGGGACAATTCAGTCACAGGCACAGGGGAACAGCTCACCTGGACTAGACTC CCACAAGGATT CAAAAACT CTCCC ACAATCTTT GG AG AAGCACT GGCCT C AG ACCTCAA GGCCT ACACCCCACCAAAT GACAACT GCGCCTTGCTGCAAT ACAT AGACGACCTTCTTT TGGCAGCCCCAACCCAAGAGGACTGTTACCAAGGAACCCAAGACCTCCTCCATCTCTTA TGGAAAGCAGGTT AT AAAGT ATCCAAAAAG AAAGCCCAAATTT GCCAT G AAAAGGTT AAA TATTTAGGCTTCATAGTAAGCCAAGGGGAACGCTGGCTTGGCAATGAATGAAAGCAGGC T GTTT GTGCACTTCCAACTCCAACCACCCGGCGCCAAAT AAGAGAATTCTT AGGGGCAG CAGGGTTCTGCCATATCTGGATCCCAAATTTCTCACTTATGGCCAAGCCCTTATATGAAG CCACAAAGGAGGGGGAAAAGGAACCCCTCCTCTGGGAGGCTGACCAGGAGAAGGCAT TT AAACAAATCAAAGAAGCCTT AACTCAGGCCCCAGCCTT AGGACT GCCAGAT AT AACT A AGCCTTTCTTTCTATATGTCCATGAATGAAAGGGAATGGCTATAGGGGTCCTGACTCAA GTCATAGGATCATGGCATCGCCCGGTGGCATACTTATCCAAACACTTGACTCTGTGGTG CGGATGGCCTCCTTGCCTTAAAGCACTAGCTGCCACCACCCTATTGGCACAAGAAGCTG ACAAACT GACTCT AGGGCAACAACT GACCATCCAGGT ACCACACTCGGTT AT AACTTT AA TGGATCAGAGAGGGCACCATTGGTTATCAAATCCAAGAATGACTCAGTACCAAGGGCTC CT AT GT GAAAATCCCCACAT AACTTT AGAAACAGT AACACCCTT AACCCAGCT ACCCTGC TCCCAGTCAAACCGGGAATCACCCTCCATGACTGTGGAAACAGTAGACGAGGTATTCTC AAGTCGGGGAGACCTTACAGACCAACCCCTCAAGGACCCAGATGTTGAATACTTCACAG ATGGAAGCAGTTTTGTACTGGAAGGGGTCCGCTGGGCTGGGTATGCAGTGGTAACATT AGACTCAGTGGTGGAGGCTCAGCCTCTGCCTACTGGAACATCAGCCCAAAAGGCAGAG CT AAT AGCCCT AACAAG AGCTCTCTT GCTGGCAAAAG ACAAAAAGAT CAAT GTTT AT ACT G ATTCCAAAT AT GCTTTT GCCACATT GCAT GTT CATGG AGCT AT AT AT AAAGAAAG AGG A CT CTT AACT GCTGG AGGCAAAGAAAT AAAGT ACAAAG AAGAAATT CT ACAGCT CTT AG AT GCTGTATGGGCCCCAAAGAAAGTAGCTGTTATGCACTGCAGGGGGCACCAAAAGGCAG GAACACTAGAGGCCAAAGGAAACAGAAAGGCAGACAGGGAGGCAAAACGGGCAGCAA T GACT ACACCGCATTTT AAAAAGGAAGCCCT AGCT AT GCCTCTCCTCCCAGAGCCTCCC CTCCCAGAGGTCCCAAGTTACTCTCCAAATGAGAAGGCCTGGTTTGCCCAAGAAACTGG AAAATATATTGAAGGAGGATGGTGGAAATTCTCTGATGGGAGGCTAGCCATTCCTGAAA TGGTGGCCCCCAAATTT GT GAAGCAATTCCATCAAGGAACTCAT AT GGGAAAAACGGCA CT AGAAACGCT ACT AGGACACCATTTCT AT GTGCCACGGCTCACT GCCATCACCCGAGC CGTTT GT GAACAAT GTCT AACTT GTGCCCAGAACAACCCAT GACAAGGGCCCACTCGGC CCCCAGGAATTCAGGAAAT AGGAGCCACACCCT GT GAAAACCT GCTT ATGGACTTCACT GAGCTGCCCCGAGCAGGGGGCT ATCGGT ACAT GTT AGT ACTT GTCTGCACCTTTTCAG GATGGGTCGAGGCTTTCCCCACCAGAACAGAGAAAGCAT GAGAAGT GACT AAAGT ACT GTT AAGAGACATT ATCCCCAGATTTGGACTGCCCCT GACTCT AGGGTCAGACAATGGAC CGGCATTT GT AGCT GAAAT AGTTCAAGAACT AACACGGCT GTT AAAAAT AAAATGGAAAT T ACACACAGCCT ACCGGCCACAGAGCTCAGGAAAAGTGGAGCACAT GAACTGGACACT CAAACAGCT ACT G AAG AAAT ATTGCCAAG AAACT CAT CT G AG ATGGG AT CAGGTCCTGC CCATGGTCCTCCTCCGAGTCAGGTGCACCCCCACCAAACAAACTGGGTATTCGCCCTAT GAGATCTTGTTCGGCCAGCCACCCCCAATCATAGGTCAAATTAAGGGTGATCTCCGTGA ACTAGGGGAATTAACTTTAAGAAGGCAAATGCAGGCTTTAGGGATAGCCATGCAAAGTG TCCATGGCTGGGT ACAGGAAAGAAT GCCCAT AAGCCT GACAGACCCAGCACACCCCTT TAAACCTGGGGACTCTGTTTGGGTTAAGAAATGGAATCCAACCACTCTGGGACCCATAT GGGAT GGGCCCCAT ACT GT AATCTT GTCCACTCCCACTGCT GTT AAAGTTGCAGGAATT GT GCCTT GGATCCACCACAGT AGTCGGCT GAAACCAGCAGCCCAGGACAAGTGGACCA GCCAACAGGACCCAGACCATCCAACCCAGCT GATCCT ACGATGGGACCAAGTT GCCAG T GAAGAT GACAACAGCCCTGCTCTGGTCACTCCGGAAGCT GACCAGTCT AT ACACGGCT GAAGCTT GAGGAGACAACAGCCCTGCTCT AGT CACCCCAGAAGCT GACT AGTCT ATGCA CGGCCGAAGCTT GAGTCAT CATCAGGGAAGT AAAT GTGGTT AGAAATCTT AAGCCT AGT AATTTTCCTT GT AAT ATT AATT ACTTT ACT ATT AACCT GTCACTTT GCT C AACCTCCTCCCC CCAGG AAAAAGCCTTTT CT GTCCAT GCTGGGTAT G AACAT GCTACT CATT ACTTT GTT CT TGCT ACTCCCCTT ATCCAT GTT AAAAGGAGAACCCTGGGAGGGAT GCCCCCACT GCACA CACACT ACGTGGTCGGGGAGCACCAT AACT AGAACCCT GTT GT ACCACACTT ATT AT GA GTGT ACAGGGACCCACCT AGG AACTT GT ACT CACAACCAG ACAACCT ACT CAGTCTGTG ACCCAGGAAAT GGCCAGCCTT AT AT AT GTT AT GACCCT AAGTCCTCACCTGGGACCT GG TTTGAAATTCATGTCGGGTCAAAGGAAGGGGATCTTCTAAACCAAACCAAGGTATTTCCC TCTGGCAAGGATGTCGTATCCTTATACTTTGATGTTTGCCAGATAACATCCATGGGCTCA CTCTTTCCCGTAATCTTCAGTTCCATGGAGTACTATAGTAGCTGCCATAAAAATAGGTAT GCACACCCTGCTT GTTCCACCGATTCCCCAGT AACAACTTGCTGGGACTGCACAACAT G GTCCACT AACCAACAAT CACT AGGGCCAATT ATGCTT ACCAAAAT ACCATT AAAACCAGA TTGT AAAACAAGCACTT GCAATCCT GT AAAT CTT ACCAT CTT AG AGCC AG AT CTGCCCAT AT GGACT ACAGGTTT AAAAGCACCGCT AGGGGCACGAGTCAGCGGT GAAGAAATTGGC CCAGG AGCCT ATGTCT AT CT AT AT ATT AT AAAGAAAACTCGGACCCGTT CAACCCAACAA TTCCGAGTTTTTGAGTCATTCTATGAGCATATCAACCAGAAGTTGCCTGAACCCCCTCCC TTGGCCAGAAACCT ATTCGCCCAACT GGCT GAAAACAT AGCCAGCAGCCT ACACATCTC CTCATGCTATGTCTGTGGGGGAACCAACATGGGAGACCAATGGCCATGGGAAGCAAGG GAGCTAATGCCCCAAGATAACTTCACTCTAACTGTCTCTTCCCCCGAACCTGCGTTCAC AAGCCAGAGCATCTGGTTCTTAAAAACCTCTATTATTGGAAGATTCTGCATTGCTCGCTG GGGAAAAGCCTTT ACAGACCCAGT AGGAGAATT AACTTGCCT AGGACAACAAT ATT ACA AT GAAACACT AGG AAAAACTTT AT GGTGGGGCAAAAAG AAT AATTCCAAAT CACCCCACC CAAGCCCATT CTCCCGTTTCCCTTCTTT AAACC ACT CTTGGT ACC AACTT G AAGCTCCAA ATACCTGGCAGGCACCCTCTGGCCTCTACTGGATCTGTGGGCCACAGGCATATTGGCA ACTGCCAGCTAAATGGTCAGGGGCCTGTGTACTGGGGACAATTAGGCCGTCCTTCTTC CT AATCCCTCT AAAGCAAGGAGAAGCCTT AGGAT ACCCCATCT AT GAT GAAACT AAAAG GAGAAACAAAAGGGGCATAACCATAGGAGATTGGAAGGACAATGAATGGCCCCCTGAA AGAATAATCCAATATTATGGCCCAGCCACCTGGGCAGAAGATGGAATGTGGGGATACC GCACCCCT ATTT ACAT GCTCAACCGCATCAT AAGGTTGCAGGCAGT ACTT GAAATCATT A CTAATGAAACTGCAAGGGCCTTAAATCTGCTGGCCCAGCAAGCCACAAAAATGAGAAAT GCCATTT ATCAAAAT AGACT GGCCTT AGACT ACCTCCT AGCCCAGGAAGGAGGAGT AT G TGGAAAGTT CAAT CT AACT AATTGCTGCCT AGAAATT GAT G ACAAT GG AAAGGTCAT CAA AGAAAT AACTGCAAAAATCCAAAAATT AGCCCAT GTTCCAGTCCAGACTTGGAAAGGAT G GTCTCCAGATTCCCTCTTCGGAGGCTGGTTTTCATCCCTTGGAGGATTTAAAACCTTAGT AGGAATAGTTCTGGCCATACTAGGAGGTTGCCTAATACTCCCTTGTCTCTTACCCCTCCT T GTCAAAAACATCCAAACAGCCAT AG AGGCTCTT GT AAACAGACAGACT ACCACACAAC T AATGGCCCT AACT AAGT ATT AACCCCTGCCAAGAAAAGAGCT ACTTCCTCTT GAAGT AA AT GAAGAT AGT GATGCTTTCT ATT AAACTTT ACTT AT AAAAAGCATCAAAGGGGGGAAT G AAGCAGGAAATATAAAAGGAAAAACAAGTAAAGGGAAAACAAGTCCTTTCCTGACCAGT CTGACTCACTCCAAAGTCCTGCTGGAGCTATGATAATTATCTGCAAGGCCAGGCAGGGG CTCCGAAGGAGTGGGCTCCAGGAGCAGGGATGAGAAAAACAAGTTCTCCTTATCAGTTT CCCT GTTT G AAATT CT CTCCCCAT AACATT ATT CTTT GTTCT GCTCTCACAACT ATTTTT G T AACT ATTT CTGCAAGTCT GT AAAG ATTTT GT AAGTT CTT GTTTTT CTTT CTGT AGCAT GG CAAGGTCACAAG ACAT GTTT AAGTAAGGTAGGCT CAT GTT GC AAATCCT GTTGT AAAACC TGTCACGGTATGATTAACTGCCTTTGTTCTGCTTCTGTAAGACTGCTTTCTCACCTCGCA GGTTTTGCGCCAAAAACCCGACTT GCCCCTGCCT GATGCAT GT AT AAAAGTCAAGCCCT GTCTTTGTTCAGGGCTCAGCCTTTGGATGTTAATCCGCTGGGCCAGTGGCCACCTAAAT AAAACCTTCCTGTTGCACCCAGTGATCTCTCCGGCCTCCTGATTCCCACAACA

SEQ ID NO: 20 H. sapiens DNA

>HERV-E whole genomic sequence Gag-Pol-Env

TATGGTAGGAGACCACCACTTCTCCTGTTGTCCTTCCCAGTTTCTCCCCAACCTCCC CTT TTCCCTAGTTTATAAGACAGGAGAAAAGGGAGAAAGCAAAAAGTTGGAAAGAAACAGAA GT AAGAT AAAT AGCT AGACGACCTTGGCGCCACCACCTGGCCCT GGTGGTT AAAAT GAT AAT AAT ATT AACCCCT GACCAAAACT ACTGGT GTT ATCTGT AAATTCCAG ACATT AT AT GA G AAAGC ACT GT AAAACTTTTT GT ACT GTT AGCT GAT GTAGGT AGCCCCC AGTCACGTTCC T CACACTT ACTT G ATCT GT GAT GACT CTTT CACGT AG ACCCCTT AG AGTT GT AAGCCCTT CAAAGGGCTAGGAATTTCTTTTTCGGGGAGCTCGGCTCTTAAGATGCGACTCTGCCGAT GCTCCTGGCCGAATAAAAACCTCTTCCTTCTTTAATCCAGTGTCTGAGGAGTTTTGTCTG CGACTCATCCTGCT ACATTTCTTGGTTCCCTGCCTGGGAAGCGAGGT AATT GATGGACG GAGGGTCGAGGCAGCCCCTTAGGTGGCTTAGGCCTGCCCTGTGGAGCATCCCTGTGG GGGACTCT GGCCAGCTT GAGT GACGCAGATCCT GAGACCACTCCCGGGT AGGCAATT G CCCCGGTGGAACGCCTCATCAGAGCAGTGCGTGGCAGGCCCCTGTGGAGGATCAACG CAGTGGCTGAACACCGGGAAGGAATGGGCACTTGGAGTCCGGACATTTGAAACTTGGT AAGACTGGTCTTTGGAACTTGCCCACTCCATCT GAGT GGAAGCGTGGCCT GATCACCCA TGGCGTGCCT GT ACCGGCACTTTGGTTTTT GTTTTT GACTT GACTT GAATT GCTT GAT AT TTTGGTTTTGGTTTT GACCTGGCTT GGACTTCTGGAT ACTCGGATTTT GGTTTT GATTCT GGTTTGGT GT AAACT GAAAAAGT GT GT GT GTGCCCTTTTT ACCT GTTCTTT GTTCT GT GG T GT GT GT GTGGT GT AAGCTTGGT GTTTT GTCTT GAGGAAACACGGGTCAGACACAAAGT AAGCCT ACTCCGCT AGGAACT AT GTT GAAAAATTTCAAGAAAGGATTT AATGGAGACT AT GGAGTT ACT AT GACACCAGGAAAACTT AGAACTTT GT GT GAAAT AGATTGGCCAGCATT A GAAGT GGGTT GGCCATCAGAAGGAAGCCT GGACAGGTCCCTT GTTTCT AAGGT ATGGC ACAAGGT AACT GGT AAGTCAGG ACACCCAG ACCAGTTTCCAT ACAT AGACACTT GGTTA CAGCTGGTTTT AGACCCCCCACAGTGGTT AAGAGGACAGGCAGCAGCAGT ACT AGT AG CAAAGGGACAGATAGCCAAGGAAGGATCCCGCTCCACCCGCTGAGGGAAATCAACTCC T G AAGTT CT GTTCGACCCAACAT CAGAAGATCCATT GCAGGAG ATGGCACC AGT G ATCC CAGTGGT GCCCTCCCCTT ACCAGGGAGAGAGGCTCCCCACTTTT GAGTCCACAGTGCT TGCGCCTCCACAAGACAAACATATCCCTAGGCCACCCAGAGTAGACAAGAGAGGAGGT GAAGCCTCGGGAGAAACCCCT CCCTTGGCAGCTCGTTT AAGACCCAAAACTGGGAT AC AAAT GCCCCT GAGAGAGCAGCGGT AT ACTGGGAT AGAT GAGGATGGACACAT GGTGGA GAGGCGT GTTTTT GT GT ACCAGCCCTTCACCTCTGCCGACCTCCTCAACTGGAAAAAT A ATACCCCATCCTATACTGAAAAGCCTCAAGCTCTAATTGATTTGCTCCAAACTATTATCC A GACCCAT AACCCCACTTGGGCT GATT GCCACCAGTT GCTCAT GT ACCTCTTT AACACAG AT GAAAGGCGGAGAGTGCTCCAAGCAGCAACT AAGTGGCT AGAGGAACATGCACCAGC T GATT ACCAAAACCCCCAAGAGT AT GT AAGGACCCAGTT ACCAGGAACCGACCCCCAGT GGGACCCAAATGAAAGAGAGGATATGCAAAGGCTAAACCGATACAGGGAAGCTCTCTT GGAAGGATTAAAGAGGGGAGCCCAGAAGGCCACAAACGTTAACAAGGTCTCTGAGGTC ATT CAAGGAAAAG AAG AAAGTCCAGCACAATT CT AT G AGAG ACT GTGT GAGGCCT ATCG T AT GT AT ACTCCCTTT GATCCCGAT AGCCCT GAAAATCAGCGCAT GATT AACATGGCTTT AGTTAGTCAAAGCGCAGAAGACATTAGAAGAAAACTGCAGAAACAGGCTGGGTTTGCAG GGAT GAACACATCACAGTT ATT AGAAAT AGCT AACCAGGT GTTT GT AAACAGGGAT GCA GTAAGCCGTAAGGAAAACCACAGAGAGAATGAACGTCAGGCCCAGCGAAACGCCGACC TGTTAGCTGCAGCAATCAGAGGGGTCCCCCCAAAGAGGCAAGGGAAGGGGGGCCCCG GGAAAGAAACTCAGCCTGGCTGTCAGAGCTTGCAGCGTAATCAGTGTGCTTATTGTAAA GAAAT AGGACATTGGAAGAACAAATGCCCTCAGCT AAAAGGAAAACAAGGT GACTCGGA GCAGGAGGCCCCAGACAAGGAGGAAGGGGCCCTGCTCAACCTGGCAGAAGGGTTATT GGACTGAGGGGGACTGGGCTCAAGGGCCCCCAAAGAGCCCATGGTCAGGATGACAGT TGGGGGT AAAGACATT GATTTTCTT GT AGAT ACTGGTGCT GAACATTCAGT AGT AACCAC CCCGGTCGCCCCCTTATCCAAAAAGACTATTGATATAATCGGAGCCACAGGAGTTTCAG CAAAGCAAGCTTTCT GCTT GCCCCGGACTT GT ACT GT AGGAGGACAT AAAGT GATTCAT CAGTTTTT GT ACATGCCT GACT GTCCCTT GCCCTT GTT GGGAAGGGACTT GCTT AGCAA GCT GAGAGCCACT ATCTCTTTT ACAAAGCAT GGCTCTTT ACAGCT AAAGTT ACCCGGAAC AGG AGTCATT AT G ACCCTT ACGGTCCCCCG AG AGG AAG AATGGAG ACTTTT CTT AACT G AGCCAGGCCAAGAGAT AAGACCAGCTCTGGCTAAGCGGT GGCCAAGAGT GT GGGCAG AAGACAACCCTCCAGGGTTGGCAGTCAACCAAGCCCCCGTACTCATAGAAGTTAAGCCT GGGGCCCAGCCAGTTAGGCAAAAACAGTATCCGGTCCCCAGAGAAGCTCTTGAAGGTA TCCAGGTCCAT CT CAAGCGCCT AAG AACCTTT GG AATT AT AGTTCCTT GTCAGT CT CCAT GGAACACTCCCCTCCTGCCTGTTCCCAAGCCAGGGACCAAGGACTACAGGCCGGTACA GGATTTGCGCTT GGTCAATCAAGCT ACAGT GACTTT ACATCCAACAGT ACCT AACCCGT A CACATTGTTGGGGTTGCTGCCAGCTGAGGACAGCTGGTTCACCTGCCTGGACCTGAAA GATGCTTTCTTT AGCATCAGATT AGCCCCT GAGAGCCAGAAGCT GTTTGCCTTTCAGT G GGAAGATCCGGAGTCAGGTGTCACTACTCAGTACACTTGGACCCGGCTTCCCCAAGGG TTCAAGAACTCCCCCACCATCTTCGGGGAGGCATTGGCTCGAGACCTCCAGAAGTTTCC CACCAGAGACCT AGGCTGCGT GTT GCTCCAGT ACGTT GAT GACCTTCTGCTGGGACAC CCCACGGCAGTCGGGTGCGCCAAAGGAACAGATGCCCTACTCCGGCACCTGGAGGAC T GT GGGT AT AAGGT GTCCAAGAAGAAAGCTCAGATCTGCAGACAGCAGGT ACGTT ACCT GGGATTTACTATCCGACAGGGGGAGCGCAGCCTGGGATCAGAAAGAAAGCAGGTCATT TGCAATCT ACCGGAGCCT AAGACCAGAAGGCAGGT GAGAGAATTCTT AGGAGCT GT GG GGTTTTGCAGACTGTGGATCCCAAACTTTGCAGTATTAGCCAAGCCTTTGTATGAGGTC ACAAAGGGGGGGGAACGGGAACCTTTTGAATGGGGATCCCAACAACAGCAAGCCTTTC AT GAGTT AAAGGAAAAACTT AT GTCAGCCCCAGCCCTGGGGCT ACCAGATCT GACAAAG CCTTTT ACATT GT AT GT GTCAGAGAGAGAAAAGAT GGCAGTTGGAGTTTT AACCCAAACT GTGGGGCCCTGGCCGAGGCCAGTGGCCTACCTCTCTAAACAACTAGACGGGGTTTCTA AAGGATGGCCCCCAT GTTT GAGGGCCTTGGCAGCAACT GCCCT GCT AGT ACAAGAAGC AGAT AAGCT GACTCTTGGGCAAAACCT GAACAT AAAGGCCCCCCATGCT GT GGT GACTT T AAT GAAT ACCAAAGGACATCATT GGCT AACGAATGCT AGACT AACT AAGT ACCAAAGCT TGCTCTGT GAAAATCCCCGT AT AACCATT GAAGTTT GT AACACCCT G AACCCCGCC ACC TTGCTCCCAGT AT CAGAG AGCCCT GTCG AGCAT AACT GTGT AGAAGT GTTGGACT CAGT TT ATTCT AGCAGACCT GACCTCCGGGACCAGCCTTGGGCATCAGT AGACTGGGAGCT AT ACGTGGATGGGAGCAGCTTCATCAACCCACAAGGAGAGAGAT GTGCAGGAT ATGCGGT GGT AACTCT GGACACT GTT ATT GAAGCCAAATCGTTGCCCCAGGGCACTTCAGCCCAGA AAGCT GAACTCATT GCTTT AATTCGGGCCTT AGAACTCAGT GAAGGT AAGACT GT AAACA TTT ACACT GACTCTCGAT AT GCCTTTTT AACCCTTCAAGTGCATGGAGCATT AT AT AAAGA AAAGGGCCT ATT GAACTCT GGGGGAAAGGACAT AAAAT ATCAACAAGAAATCTTGCAATT ATTAGAAGCAGTATGGAAACCCCACAAGGTGGCAGTTATGCATTGCAGAGGACACCAG CGAGCTTCCACCTTGGTGGGTTTAGGGAATTCCCGCGCTGACTCAGAGGCTCGAAAAG CAGCATCTACCCCCTTCCGGGCATCAGTCACAGCCCCCCTGCTCCCTCAAGCACCTGA TCTTGTACCTACTTATTCTAAAGAAGAAAAGGACTTTCTCCAGGCAGAGGGAGGACAAG T GAT AGAGGAAGGATGGATTCGGTT ACCAGATGGGAGAGT AGCT GT GCCACAGCT GCT AGGAGCCGCAGTT GT ACTGGCT GTGCAT GAAACCACCCATCT AGGCCAGGAGTCACTT G AAAAGTT GTT AGGCTGGT ATTT CT ACAT CT C ACATTT GT CAGCCCTTGCCAAAACAGT G ACGCAGCGGTGTGTTACCTGCCGACAGCATAATGCGAGGCAAGGTCCAGCTGTTCCAC CCGGCATACAAGCTTATGGAGCAGCCCCCTTTGAAGATCTCCAGGTGGACTTCACAGA GATGCCAAAAT GTGGAGGT AACAAGT ATTT ACTAGTTCTT GT GT GT ACCT ACTCTGGGT G GGTGGAGGCTT ATCCAACACGAACT GAGAAAGCTCGT GAAGT AACCCGT GTGCTTCTTC GAGATCTTATTCCTAGGTTTGGACTGCCCTTACGGATCGGCTCAGATAATGGGCCGGCA TTT GT GGCT GACTT GGT ACAGAAGACAGCAAAGGT ATT GGGGATCACAT GGAAACT ACA TGCCGCCTACCGACCTCAGAGTTCCGGAAAGGTGGAGCGAATGAATCGGACTATCAAA AAT AGTTT AGGGAAAGT AT GTCAGGAAACAGGATT AAAAT GGAT ACAGGCTCTCCCT AT GGT ATT GTTT AAAATT AG AT GT ACCCCTTCT AAAAGAACAGG AT ATTCCCCTT AT G AAAT A TT AT ATCAT AGGCCCCCT CCT AT ATTGCGGGGACTTCCAGGCACTCCCCGAGAGTT AGG T G AAATT G AGTT ACAGCGACAGCT ACAGGCTTT AGG AAAAATT ACACAAACAAT CTCAGC CTGGGTAAATGAGAGATGCCCTGTTAGCTTATTCTCCCCAGTTCACCCTTTCTCCCCAG GT GATCGAGT GT GGATCAAGGACTGGAACGT AGCCTCTTT GT GGCCACGGTGGAAAGG ACCCCAGACTGTCATCCTGACCACTCCCACCGCTGTGAAGGTAGAAGGAATCCCAGCC TGGATCCACCACAGCCAT GT AAAACCTGCAGCGCCT GAAACCTGGGAGGCAAGACCAA GCCCAGACAACCCCT GCAAAGT GACCCT GAAGAAGACGACAAGCCCTGCTCCAGTCAC ACCCGGAAGCTGACTGGTCCACGCACGGCCGAAGCATGAGGAAGCTCATCGTGGGAC T CATTTTT CTT AAATTTT GG ACTT AT ACAGT AAGGGCTT CAACT G ACCTT ACT CAAACT GG GGACT GTTCCCAGTGT ATT CAT CAGGTCACT G AGGT AGGACAACAAGTT AAAAC AAT CTT TCTGTT CT AT AGTT ATT AT G AAT GTAT AGG AACTTT AAAAGG AACTT GTTT GTAT AAT GCC ACTCAGT ACAAGGT AT GT AGCCCAGGAAAT GACCGACCT GAT GT GT GTT AT AACCCATC T GAGCCCCCTGCAACCACCGTTTTT GAAAT AAGATT AAGAACTGGCCTTTTCCT AGGT GA T ACAAGT AAAAT AAT AACT AGAACAG AAG AAAAAGG AATCCCCAAACAAAT AACTTT AAG ATTT GAT GCTT GTGCAGCCATT AAT AGT AAAAAGCT AGGAAT AGGAT GT GGTTCTCTT AA CTGGGAAAGGAGCT ACAGAGT AGAAAAT AAAT AT GTTT GTCAT GAGTCAGGGGTTT GT G AAAATTGTGCCTATTGGCCATGTGTTATTTGGGCTACTTGGAAAAAGAACAAAAAGGACC CGGTTT ATCTTCAGAAGGGGGAAGCCAACCCCTCCT GTGCTGCCGGTCACT GT AACCC ACT AGAACT AAT AATT ACCAATCCCCT AGATCCCCATTGGAAAAAGGGAGAACGT GT AAC CCTGGGGATCAATGGGACAGGGTTAAACCCCCAAGTTGCCATTTTAATTAGAGGGGAG GTCCACAAGTGCTCTCCCAAACCAGTATTTCAAACCTTTTATGAGGAGCTGAATCTGCCA GCACC AG AACTTCCG AAAAAG ACAAAAAATTT GTTT CTCCAATT AGC AG AAAAT GT AGCT CATTCCCTT AAT GTT ACTTCTT GTT AT GT AT GCGGGGGAACCACT ATCGGAGACCGAT G GCCTTGGGAAGCCCGAGAGTT GGTGCCT ACT GATCCAGCTCCT GAT AT AATTCCAGTTC AGAAGGCCCAAGCT AGCAACTTCT GGGTCCT AAAAACCTCAATT ATT GGACAAT ACT GC AT AGCT AGAGAAGGGAAAGACTTT ATCATCCCT GT AGGAAAGCTT AATT GT AT AGGACA G AAGTT GT AT AACAGC ACAAC AAAG ACAATT ACTT GGTGGGGCCT AAACCACACT G AAA AG AATCCATTT AGT AAATTTT CT AAATT AAAAACTGCTTGGGCT CATCCAGAAT CT CAT CA GGACTGGACAGCTCCCGCT GGACT AT ACTGGAT AT GTGGGCACAGAGCCT ACATTCGG TT ACCT AAT AAATGGGCAGGCAGTT GT GTT ATT GGCACT ATT AAGCCATCCTTTTTCTT AT T ACCCAT AAAAACAGGT G AGCTCCT AGGTTTCCCT GTCT ATGCCTCCCG AGAAAAG AGA AGCAT AGCT AT AGGAAACTGGAAAGAT AAT GAGT GGCCCCCT GAAAGAATCAT ACAGT A TTATGGGCCTGCCACATGGGCACAAGACGGCTCATGGGGATACCGAACCCCCATCTAC AT GCTCAACCGGATCAT ACGGTT ACAGGCT GTCTT AGAAAT AATT ACT AAT GAAACTGGC AGAGCTTT GACT GTTTT AGCTTGGCAAGAAACCCAAAT GAGGAAT GCT ATCT ATCAGAAT AGACTGGCCTT AGACT ACTTGCT AGCAGCT GAAGGAGGAGTTT GTGGAAAATTT AACTT AACCAATTGCT GTCT ACAAAT AG AT GAT CAAGG ACAAGT GGTT G AAAACAT AGTCAG AGA CAT GACAAAGCT GGCACAT GTGCCT GT ACAGGTTT GGCACGAGTTT GATCCT GAGTCTT T ATTT GGAAAATGGTTTCCAGCT AT AGGAGGATTT AAAACCCTCATT GT AGGT GT ATT AA T AGT AAT AGGAACCT GCTT GCTGCTCCCCT GTTTGCT ACCCTTGCTTTTTCAAAT GAT AA AAAGCTTT GTTGCT ACTTT AGTT CAT CAAAAT ACTT CAGCACAAGT GT ATT AT AT G AAT CA CT ATCGCT CT AT CT C ACAAAAAG ACTCAG AAAGT G AGG AT GAG AGT G AG AACTCCCACT AAT AAAAAGT GAAAATT CT CAAAGGGGGGG AAT ATGGT ACGAG ACCACCACTT CTCCTG TTGTCCTTCCCAGTTTCTCCCCAACCTCCCCTTTTCCCTAGTTTATAAGACAGGAGAAAA GGGAGAAAGCAAAAAGTTGGAAAGAAACAGAAGAAAGAT AAAT AGCT AGACGACCTT GG CGCCACCACCT GGCCCTGGT GGTT AAAAT GAT AAT AAT ATT AACCCCT GACCAAAACT A CTGGT GTT ATCTGT AAATTCCAG ACATT GTGT G AG AAAGCACT GT AAAACTTTTT GTAGT GTT AGCT GAT GTAGGT AGCCC ACAGTCACATTCCT CACACTT ACTT GAT CT ATT AT G ACT CTTTCACGTAGACCCCTTAGAGTTGTAAGCCCTTCAAAGGGCTAGGAATTTCTTTTTCGG GGAGCTCGGCTCTTAAGATGCGAGTCTGCTGATGCTCCCGGCCGAATAAAAAACCTCTT CCTTCTTTAATCCGGTGTCTCAGGAGTTTTGTCTGCGACTCGTCCTGCTACA

SEQ ID NO: 21 H. sapiens DNA

>HERV-V whole genomic sequence Gag-Env

ACAGACTCCTTCTTTTCAGGAGCCCACTCGGTTCTGTCGTTCAGGGTGTCGCTTCTT TCT G AGCTCCT GTCT CTTT AAAT G AAGGGCATTT ACCCTTT AACT CTTT CTGCGC AT CT CTT G ACTGAATCCAAGAAGACCAAGAACCAGAGGACTTCCACACCCCTCTGGGTAACATCTGG TGTTTTCACCTGGTTACCTGGTTACCTCGCCTGGTTATCCAGCTATCAACATTTCTGGCA TCTCCAGTTGGATACATCAGTCTCAAGTGAAACTGTGGGAAGGTCCCGAAGAACCACAG AAGAACAACAGAATTCAGCACCT GAGCATTCTT GT GAGCCACTGGAGAACTT AAAATTC CACTT CAAGT G AAAAG AT AAGT AAAGCCTT CT CT CT GTT CACCCAAAACT AAAGTCAAT C TCAGTACGGGGAATCTTGGTTGCGGTGGCATTGGTTCTTCTCCTTATTTTGACCCAACT GGCATGCCACCTGAAGTCCCGATAACAGCCTGATTTCTCACTAAACACTCCATCGAACC ACTT CATT ATTT GTCTCTCCT ATTTT CAGCACTTTCCTTTT GCTTT CACAAAGCTT AAGGG AGAAT CAGCT AT G ACAG AG AAATTCCTTTTCCTTT AT CTTTCCCTCCTTCCC ATGCCCCT ACT CT CACAGGCACAGT GG AAT G AAAATTCCCTT GT CAGTTTTTCCAAAAT AATTGCTT C GGGAAACCATCTAAGCAACTGTTGGATCTGCCACAACTTCATCACCAGGTCCTCATCTT ACCAAT AT ATTTTGGT AAGAAATTTTTCTTT AAACCT AACATTTGGTTCAGGAATCCCT GA AGGCCAACATAAATCTGTTCCGCTCCAGGTTTCGCTTGCTAACTCAGCGCACCAAGTCC CCTGCCTGGAT CT CACTCCACCTTT CAAT CAAAGCT CT AAAACTT CTTT CT ATTT CT ACAA CTGCT CTT CT CT AAACCAAACCT GTT GTCC ATGCCCT G AAGGACACT GT G AC AGG AAGA ACACCTCTGAGGAGGGATTCCCCAGTCCCACCATCCATCCCATGAGCTTCTCCCCAGCA GGCTGCCACCCT AACTT GACTCACT GGT GTCCAGCT AAACAAAT GAACGATT ATCGAGA CAAGTCACCCCAAAACCGCTGTGCAGCTTGGGAAGGAAAAGAGCTAATCACATGGAGG GTTCTATATTCGCTTCCCAAGGCACACACTGTCCCCACATGGCCAAAATCTACTGTTCCC CTGGGAGGGCCTCTATCCCCTGCATGCAATCAAACTATTCCAGCAGGGTGGAAATCGC AGTTACACAAGTGGTTCGACAGCCACATCCCCCGGTGGGCCTGTACCCCTCCTGGCTA TGT ATTTTT ATGT GGGCCACAAAAAAAT AAACT GCCCTTT GATGGAAGTCCT AAGAT AAC CT ATTCAACCCCCCCT GTGGCAAACCTCT ACACTTGCATT AAT AACATCCAACAT ACGGG AGAATGTGCTGTGGGACTTTTGGGACCACGGGGGATAGGTGTGACCATTTATAACACCA CCCAACCCAGACAGAAAAGAGCTCT GGGTCT AAT ACT GGCAGGGATGGGTGCGGCCAT AGGAATGATCGCCCCATGGGGAGGGTTCACTTATCATGATGTCACCCTCAGAAATCTCT CCAGACAAAT AGACAACAT AGCT AAGAGT ACCAGAGAT AGCATCTCT AAACTCAAGGCC TCCAT AG ATT CT CT AGCAAAT GT AGTCAT GG ACAACAGATTGGCCTT AG ATT ACCT CTT A GCAGAGCAGGGT GGAGTCT GTGCAGT GATCAAT AAATCCT GTTGCGTTT AT GTCAAT AA CAGTGGGGCGATAGAGGAGGATATAAAAAAGATCTATGATGAGGCTACGTGGCTCCAT GACTTTGGAAAAGGAGGTGCTTCAGCAAGGGCCATCTGGGAGGCTGTGAAGTCTGCCC TCCCCTCCCTCAACTGGTTTGTCCCTTTACTGGGACCAGCAACAGTTATACTCTTACTTT TCCT CTTTGGCCCTT GTTT CTTT AATTT ACT GATT AAGT GTGTCT CTT CT AGGAT AAAGCA ATTTCACATGAAGTCCCCCCAAATGGAAAGATATCAGCTATCTGTCATTGGAGGCCCCA GCACCT AT AAGCACATCTCCCCCTT GGAT GCCAGT GGGCAAAGATTCCGGGAAACT AT G GAGGAATTTTCTCTCTGAGACAGAGCAAGAGAGGGAGACCCTGATGACTTCTTCGCCCC ATGTCAGCAGGAAGTAGTTACAGAAGACCCACGACGTCCTTACAACCAGAGCTTTTCAG GGTCTCCATCTCTTGAGGAGGGAAATATTAGGGTAGGCAGGTAGGCAGGCATGAGCAG GCAAGAGAGCCCTT GGGAAAGGAATCTTT AGAAACGCAGCCCACT GAT AGCTTCCTTGG T G ATGCTGCCCACAG ACAGTCAGCACTT CT CT AAT AACCCATCCT AG AACA

SEQ ID NO: 22 H. sapiens protein

>HERV-F(c)2 consensus protein sequence Gag

MGSTQSKIVQNTPLGCLLRNLPTLQLDQDLKRKRLIFFCTVAWPQYTLDNQSRWPPE GTLN

FNILNDLTNFCQKQGKWSEIKYVQGFWDLHSPPDLCAPCSLVQVLLAKTSPKTSPDP DKDD

LSPLSDPIDNLSSPPLQTAAHALPPPYASPPPSAPPSGHAPPTSSRVPPSPITPPPP PPPSSP

PPPPLPSPAPPKSPVAAHTQARPALLAPLREVAGAEGIVRVHVPFSLVDLSKIERHL GSFSTN

PTLFTKEFHYLCQVYDLTWHDIHIILTSTLSPEERERILIAARQHANQLHLTDPNVP VGTQAVP

STDPEWDYQVGQAGRRRRDIMVQCLLAGMQVASNKSVNFDKLKEIVQYPDENPAVFL NRL

TDALVHYTRLDPASPAGATILATYFISQSATDIRKKLKKAEEGLQTPIQDLVKLAFK VFNSREE

AAEVQQQARLKQKVQLQTQALAAAVQPAFPKSPGKKGRGTISRAPSGACFKCGNSGH WA

SRCPSQQQPSCLPYNCFKCGNPGHWAKQCPNPKPPMRPCPNCRQMGHWRSDCPGLRA

AAVSPHGDPSPDGEGTFQLLQLDDD

SEQ ID NO: 23 H. sapiens protein

>HERV-F(c)1 consensus protein sequence Gag

MGGAQSKIDPKTPLGCLLANFEALGLSMDLKRKRLIFFCLVAWPQYKLDNQSRWPPE GTFD

FQILQDLDNLCRRQGKWSEVPYVQAFWDLRSRPDLCAKCSLGQVLLAKASPSNKEPD SSP

LSEPPEALALPPLPAALPPPYPGSSGPTPTAPPLPPTPPSSPANPPASALPPPSPVS AHTRS

KTDLLCLLREVAGAEGVVRVH VPFSLTDLSKI EKRPGSFSAN PTLYI KQFRYLCQAYDLTWR

DLHIILTSTLSPEERERVQAVARQHADQIHLTDPAMPVGTLAVPAAEPDWDYQAGQT GRRR

RDQMVQCLLASMQAASNKTVNFDKLREIIQGSDENPAVFLNCLTEALIQYTRLDPTS PAGAT

VLATHVISQSAGDIRKKLKKVEEGPQTPIQDLVKMAFRVYNSREETAEAQRQARLKQ KVQFQ

TQALVAAPRLAGSGSQPKGGSGHRAPPGACFKCGNEGHWAWQCPYPKEPTRPCPNCH Q

MGHWKSECPSVGASTVPLRCENSETTGGAFQLLSMDDD

SEQ ID NO: 24 Mus musculus siRNA ID: S523645 Sense: Sequence (5 ^' ->3 ^' )

CGCUUGGUCCAGUUUGUAAtt

SEQ ID NO: 25 Mus musculus siRNA ID: S523645 MuERV Env P10404 Antisense: Sequence (5 ^' ->3 ^' )

UUACAAACUGGACCAAGCGgt

SEQ ID NO: 26 Mus musculus siRNA ID: S523644 MuERV Env P10404 Sense: Sequence (5 ^' ->3 ^' )

CGGGCAUACUGUACCAACAtt

SEQ ID NO: 27 Mus musculus siRNA ID: S523644 MuERV Env P10404

Antisense: Sequence (5 ^' ->3 ^' ) UGUUGGUACAGUAUGCCCGgg SEQ ID NO: 28 Mus musculus siRNA ID: S523643 MuERV Env P10404 Sense: Sequence (5 ^' ->3 ^' )

CCAACUUAAUGACAGGACAtt

SEQ ID NO: 29 Mus musculus siRNA ID: S523643 MuERV Env P10404

Antisense: Sequence (5 ^' ->3 ^' ) UGUCCUGUCAUUAAGUUGGta

SEQ ID NO: 30 Mus musculus siRNA ID: S529374 MuERV Gag Sense: Sequence (5 ^' ->3 ^' )

GGAACCACCUAGUUCUCUAtt

SEQ ID NO: 31 Mus musculus siRNA ID: S529374 MuERV Gag Antisense: Sequence (5 ^' ->3 ^' )

UAGAGAACUAGGUGGUUCCta

SEQ ID NO: 32 Mus musculus siRNA ID: S529085 MuERV Gag Sense: Sequence (5 ^' ->3 ^' )

GGUCGAAAGUUAGAGCGGUtt

SEQ ID NO: 33 Mus musculus siRNA ID: S529085 MuERV Gag Antisense: Sequence (5 ^' ->3 ^' )

ACCGCUCUAACUUUCGACCaa

SEQ ID NO: 34 Mus musculus siRNA ID: S535486 MuERV Gag Sense: Sequence (5 ^' ->3 ^' )

AGUCCGUAGAUGUCAAGAAtt

SEQ ID NO: 35 Mus musculus siRNA ID: S535486 MuERV Gag Antisense: Sequence (5 ^' ->3 ^' )

UUCUUGACAUCUACGGACUga

SEQ ID NO: 36 Mus musculus siRNA ID: 5406 XPR1 Sense: Sequence (5 ^' ->3 ^' )

GGAUAUGCUGUAUUCAGCUtt

SEQ ID NO: 37 Mus musculus siRNA ID: 5406 XPR1 Antisense: Sequence (5 ^' ->3 ^' ) AGCUGAAUACAGCAUAUCCtt

SEQ ID NO: 38 Mus musculus siRNA ID: 5493 XPR1 Sense: Sequence (5 ^' ->3 ^' ) GGUAUUGAUAGAAGACACAtt

SEQ ID NO: 39 Mus musculus siRNA ID: 5493 XPR1 Antisense: Sequence (5 ^' ->3 ^' ) UGUGUCUUCUAUCAAUACCtt

SEQ ID NO: 40 Mus musculus siRNA ID: 60216 Slc7a1 (mCAT-1) Sense: Sequence (5 ^' ->3 ^' ) GGACUGUUAACUCUUGGCGtt

SEQ ID NO: 41 Mus musculus siRNA ID: 60216 Slc7a1 (mCAT-1) Antisense: Sequence (5 ^' ->3 ^' ) CGCCAAG AG U UAACAG U CCtg

HERV H (SEQ ID NOs. 42-44)

SEQ ID NO: 42 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) GCAAACAACUGCUGGCUUUuu

SEQ ID NO: 43 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) GCAAAGACCCACCGGAAU uu

SEQ ID NO: 44 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) CGGCAAAGACCCACCGGAAuu

HERV K

SEQ ID NO: 45 Homo sapiens shRNA

Sense: Sequence (5 ^' ->3 ^' )

CCT G AAC ATCC AG AATT AT

HERV T (SEQ ID NOs. 46-48) SEQ ID NO: 46 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) AGGAGAAACUGGACUAAUAuu

SEQ ID NO: 47 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) GGGUGAAGCCAUUAGAUUAuu

SEQ ID NO: 48 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) ACGCAUAGCUUCUGUCAAAuu

HERV W (SEQ ID NOs. 49-50)

SEQ ID NO: 49 Homo sapiens shRNA

Sense: Sequence (5 ^' ->3 ^' ) GCAGCGTCCCGGAAATATTGA

SEQ ID NO: 50 Homo sapiens shRNA

Sense: Sequence (5 ^' ->3 ^' ) GGAAATCTCAGCTGCACAACC

HERV FRD/Syncytin2 (SEQ ID NOs. 51-53)

SEQ ID NO: 51 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) CCAUAAAGCUCCAGACGAAuu

SEQ ID NO: 52 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) GGGUAAAUCAAUCAGGAAAuu

SEQ ID NO: 53 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) GGAGCUAACCAGAGCCAAAuu

HERV R/ERV3

SEQ ID NO: 54 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) AGGCAUAACUAUAGGAGAU

HERV R(b) (SEQ ID NOs. 55-57)

SEQ ID NO: 55 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) GCCAAACACAACTCGTGTT

SEQ ID NO: 56 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) GCCGACAT ACT AT ACT GTT

SEQ ID NO: 57 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) GCTTCCCTCAGGTTGGTTA

HERV F(c)2 (SEQ ID NOs. 58-60)

SEQ ID NO: 58 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) GCAATACCAGCTGGGTCAA

SEQ ID NO: 59 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) GCACTGGTGCAATATCCAT

SEQ ID NO: 60 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' )

GGT GT AGATGGAGGACT AT

HERV E (SEQ ID NOs. 61-63)

SEQ ID NO: 61 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' )

CCG ACCCG AT GTGT GTT AT

SEQ ID NO: 62 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) GCTCGT GCAGCCATT AAT A

SEQ ID NO: 63 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' )

GCAGGAAAT GT AGCTCATT

HERV P(b1)/HERV IP (SEQ ID NOs. 64-66)

SEQ ID NO: 64 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' )

GOT AGCC ACCTCATT ATT A

SEQ ID NO: 65 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) GCTTGCAGCAGCAGAGAAA

SEQ ID NO: 66 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' )

CCAG ATGCCAAGTTT ACTT

HERV V (SEQ ID NOs. 67-69)

SEQ ID NO: 67 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' )

T CAACTGGTTT GTCCCTTT

SEQ ID NO: 68 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) GGCCCTTGTTTCTTTAATT

SEQ ID NO: 69 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) GGGCAAAGATTCCGGGAAA

HERV MER34 (SEQ ID NOs. 70-72)

SEQ ID NO: 70 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) GCACCTTCATGCCCTCTAT

SEQ ID NO: 71 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' ) GCAGATGCCAGCATAACTA SEQ ID NO: 72 Homo sapiens siRNA

Sense: Sequence (5 ^' ->3 ^' )

CCA GAT ACCT CACCTT AAA

Primers for qRT-PCR (SEQ ID NOs. 73-92)

Numbers in parentheses indicate start binding location to the respective gene

SEQ ID NO: 73

DNA artificial qRT PCR product size 149bp hActB fwd

ACTCTTCCAGCCTTCCTTCC (780)

SEQ ID NO: 74

DNA artificial qRT PCR product size 149bp hActB rev

CAATGCCAGGGTACATGGTG (909)

SEQ ID NO: 75 DNA artificial HERV H1-3 qRT PCR product size 113bp HERV H1-3 fwd tccccagacatttcacatcag (358)

SEQ ID NO: 76 DNA artificial HERV H1-3 qRT PCR product size 113bp HERV H1-3 Rev gagcggccacaggaatagta (471)

SEQ ID NO: 77 DNA artificial HERV K 1-6 qRT PCR product size 142bp HERV K 1-6 fwd2

TGGCCAATAGTGCGGTGATA (740)

SEQ ID NO: 78 DNA artificial HERV K 1-6 qRT PCR product size 142bp HERV K 1-6 Rev2

TCGCTATCAACAGCTGGACT (862) SEQ ID NO: 79 DNA artificial HERV T qRT PCR product size 94bp HERV T Fwd ccaggatttgatgttggg (640)

SEQ ID NO: 80 DNA artificial HERV T qRT PCR product size 94bp HERV T Rev ggtgtttctggaatatagggtcac (734)

SEQ ID NO: 81 DNA artificial HERV W qRT PCR product size 187bp HERV W Fwd cccatcgtataggagtctt (146)

SEQ ID NO: 82 DNA artificial HERV W qRT PCR product size 187bp HERV W Rev ccccatcagacataccagtt (333)

SEQ ID NO: 83 DNA artificial HERV FRD qRT PCR product size 94bp HERV FRD Fwd gcctgcaaatagtcttcttt (261)

SEQ ID NO: 84 DNA artificial HERV FRD qRT PCR product size 94bp HERV FRD Rev ataggggctattcccattag (355)

SEQ ID NO: 85 DNA artificial HERV R qRT PCR product size 121 bp HERV R Fwd ccatgggaagcaagggaact (793) SEQ ID NO: 86 DNA artificial HERV R qRT PCR product size 121 bp HERV R Rev ctttccccagcgagcaatac (914)

SEQ ID NO: 87 DNA artificial HERV R(b) qRT PCR product size 145bp HERV R(b) Fwd ggacagtgccgacatactat (709)

SEQ ID NO: 88 DNA artificial HERV R(b) qRT PCR product size 145bp HERV R(b) Rev tagagtgcagcatcctaacc (854)

SEQ ID NO: 89 DNA artificial HERV F(c)2 qRT PCR product size 174bp HERV F(c)2 Fwd atggaggactatatgagcacaa (590)

SEQ ID NO: 90 DNA artificial HERV F(c)2 qRT PCR product size 174bp HERV F(c)2 Rev attaaagttaaccacgagaagc (764)

SEQ ID NO: 91 DNA artificial HERV F(c)1 qRT PCR product size 84bp HERV F(c)1 Fwd gctacaccactcctaactcatcct (908)

SEQ ID NO: 92 DNA artificial HERV F(c)1 qRT PCR product size 84bp HERV F(c)1 Rev ttgtaagggtgaagttacaccaga (992)

SEQ ID NO: 93 DNA

Mus musculus mutated

MuERV Env polyprotein P10404, variable regions VRA, VRC and VRB in the surface domain SU that determine receptor usage by different X/P-MuLV subtypes MCF247. Env protein of a typical polytropic MuLV, MCF 247, variable regions VRA, VRC and VRB in the surface domain SU that determine receptor usage by different X/P-MuLV subtypes GDDWDETGLG CRTPGGRKRA RTFDFHTVPT GCRGNTPQNQ GPCYDSSAVS

SDIKGATPGGR (61 aac)

SEQ ID NO: 94 DNA

Mus musculus mutated P 10404 (MuERV Env)

Xaa=R, MuERV Env polyprotein P10404, variable regions VRA, VRC and VRB in the surface domain SU that determine receptor usage by different X/P-MuLV subtypes, Xaa can be any naturally occurring amino acid

GDDWDETGLG CRTPGGRKRA RTFDFHTVPT GCRXNTPQNQ GPCYDSSAVS

SDIKGATPGGR (61 aac)

SEQ ID NO: 95

DNA artificial primer: Syncytin-1 fwd ccgctcgaga gcggtcgtcg gccaac (26 bp)

SEQ ID NO: 96

DNA artificial primer: Syncytin-1 rev gaagatctcc ttcccagcta ggcttaggg (29 bp)

SEQ ID NO: 97

DNA artificial pSIH-shRNA-Syn ggccctccct tatcatatt (19bp)

SEQ ID NO: 98

DNA artificial loop sequence to silence Syncytin-1 cttcctgtca ga (12bp)

SEQ ID NO: 99 DNA

Homo sapiens SLC1A4

ATGGAGAAGAGCAACGAGACCAACGGCTACCTTGACAGCGCTCAGGCGGGGCCTGCG

GCCGGGCCCGGAGCTCCGGGGAC

CGCGGCGGGACGCGCACGGCGTTGCGCGGGCTTCCTGCGGCGCCAAGCGCTGGTGC

TGCTCACCGTGTCCGGGGTGCTGG

CGGGCGCGGGCCTGGGCGCGGCGTTGCGCGGGCTCAGCCTGAGCCGCACGCAGGTC

ACCTACCTGGCCTTCCCCGGCGAG

ATGCTGCTCCGCATGCTGCGCATGATCATCCTGCCGCTGGTGGTCTGCAGCCTGGTG T

CGGGCGCCGCCTCGCTCGATGC

CAGCTGCCTCGGGCGTCTGGGCGGCATCGCTGTCGCCTACTTTGGCCTCACCACACT G

AGTGCCTCGGCGCTCGCCGTGG

CCTTGGCGTTCATCATCAAGCCAGGATCCGGTGCGCAGACCCTTCAGTCCAGCGACC T

GGGGCTGGAGGACTCGGGGCCT

CCTCCTGTCCCCAAAGAGACGGTGGACTCTTTCCTCGACCTGGCCAGAAACCTGTTT CC

CTCCAATCTTGTGGTTGCAGC

TTTCCGT ACGT ATGCAACCG ATT AT AAAGTCGT GACCCAGAACAGC AGCT CTGGAAAT G T AACCC AT G AAAAG ATCCCCA

T AGGCACT GAGAT AGAAGGGAT GAACATTTT AGGATT GGTCCT GTTT GCTCTGGT GTT A GGAGTGGCCTTAAAGAAACTA

GGCTCCGAAGGAGAAGACCTCATCCGTTTCTTCAATTCCCTCAACGAGGCGACGATG GT

GCTGGTGTCCTGGATTATGTG

GTACGTACCTGTGGGCATCATGTTCCTTGTTGGAAGCAAGATCGTGGAAATGAAAGA CA

TCATCGTGCTGGTGACCAGCC

TGGGGAAATACATCTTCGCATCTATATTGGGCCATGTTATTCATGGAGGAATTGTTC TGC CACTT ATTT ATTTT GTTTT C

ACACGAAAAAACCCATTCAGATTCCTCCTGGGCCTCCTCGCCCCATTTGCGACAGCA TT

TGCTACCTGCTCCAGCTCAGC

GACCCTTCCCTCT AT GAT GAAGTGCATT GAAGAGAACAATGGT GTGGACAAGAGGATCA GCAGGTTTATTCTCCCCATCG

GGGCCACCGTGAACATGGACGGAGCAGCCATCTTCCAGTGTGTGGCCGCGGTGTTCA T TGCGCAACTCAACAACGT AGAG

CTCAACGCAGGACAGATTTTCACCATTCTAGTGACTGCCACAGCGTCCAGTGTTGGA GC

AGCAGGCGTGCCAGCTGGAGG

GGTCCTCACCATTGCCATTATCCTGGAGGCCATTGGGCTGCCTACTCATGACCTGCC TC

TGATCCTGGCTGTGGACTGGA

TTGTGGACCGGACCACCACGGTGGTGAATGTGGAAGGGGATGCCCTGGGTGCAGGCA TT CTCC ACCACCT G AAT CAGAAG GCAACAAAGAAAGGCGAGCAGGAACTTGCTGAGGTGAAAGTGGAAGCCATCCCCAACT

GCAAGTCTGAGGAGGAGACATC

GCCCCTGGTGACACACCAGAACCCCGCTGGCCCCGTGGCCAGTGCCCCAGAACTGGA ATCCAAGGAGTCGGTTCTGTGA (1599 bp)

SEQ ID NO: 100 DNA

Homo sapiens SLC1A5

ATGGTGGCCGATCCTCCTCGAGACTCCAAGGGGCTCGCAGCGGCGGAGCCCACCGCC

AACGGGGGCCTGGCGCTGGCCTC

CATCGAGGACCAAGGCGCGGCAGCAGGCGGCTACTGCGGTTCCCGGGACCAGGTGCG

CCGCTGCCTTCGAGCCAACCTGC

TTGTGCTGCTGACAGTGGTGGCCGTGGTGGCCGGCGTGGCGCTGGGACTGGGGGTGT

CGGGGGCCGGGGGTGCGCTGGCG

TTGGGCCCGGAGCGCTTGAGCGCCTTCGTCTTCCCGGGCGAGCTGCTGCTGCGTCTG

CTGCGGATGATCATCTTGCCGCT

GGTGGTGTGCAGCTTGATCGGCGGCGCCGCCAGCCTGGACCCCGGCGCGCTCGGCC

GTCTGGGCGCCTGGGCGCTGCTCT

TTTTCCTGGTCACCACGCTGCTGGCGTCGGCGCTCGGAGTGGGCTTGGCGCTGGCTC T

GCAGCCGGGCGCCGCCTCCGCC

GCCATCAACGCCTCCGTGGGAGCCGCGGGCAGTGCCGAAAATGCCCCCAGCAAGGAG

GTGCTCGATTCGTTCCTGGATCT

TGCGAGAAATATCTTCCCTTCCAACCTGGTGTCAGCAGCCTTTCGCTCATACTCTAC CAC CT AT GAAG AGAGGAAT AT CA

CCGGAACCAGGGTGAAGGTGCCCGTGGGGCAGGAGGTGGAGGGGATGAACATCCTGG GCTTGGT AGT GTTT GCC ATCGTC

TTTGGTGTGGCGCTGCGGAAGCTGGGGCCTGAAGGGGAGCTGCTTATCCGCTTCTTC A

ACTCCTTCAATGAGGCCACCAT

GGTTCTGGTCTCCTGGATCATGTGGTACGCCCCTGTGGGCATCATGTTCCTGGTGGC T

GGCAAGATCGTGGAGATGGAGG

ATGTGGGTTTACTCTTTGCCCGCCTTGGCAAGTACATTCTGTGCTGCCTGCTGGGTC AC

GCCATCCATGGGCTCCTGGTA

CTGCCCCTCATCTACTTCCTCTTCACCCGCAAAAACCCCTACCGCTTCCTGTGGGGC AT

CGTGACGCCGCTGGCCACTGC

CTTTGGGACCTCTTCCAGTTCCGCCACGCT GCCGCT GAT GAT GAAGTGCGT GGAGGAG AATAATGGCGTGGCCAAGCACA

TCAGCCGTTTCATCCTGCCCATCGGCGCCACCGTCAACATGGACGGTGCCGCGCTCT T

CCAGTGCGTGGCCGCAGTGTTC

ATTGCACAGCTCAGCCAGCAGTCCTTGGACTTCGTAAAGATCATCACCATCCTGGTC AC

GGCCACAGCGTCCAGCGTGGG

GGCAGCGGGCATCCCTGCTGGAGGTGTCCTCACTCTGGCCATCATCCTCGAAGCAGT C

AACCTCCCGGTCGACCATATCT

CCTTGATCCTGGCTGTGGACTGGCTAGTCGACCGGTCCTGTACCGTCCTCAATGTAG AA

GGTGACGCTCTGGGGGCAGGA

CTCCTCC AAAATT ACGTGGACCGT ACGG AGTCG AGAAGCACAG AGCCT G AGTT GAT ACA AGT GAAGAGT GAGCTGCCCCT

GGATCCGCTGCCACTCCCCACTGAGGAAGGAAACCCCCTCCTCAAACACTATCGGGG G

CCCGCAGGGGATGCCACGGTCG

CCT CT G AG AAGG AAT CAGTCAT GTAG (1626bp)

SEQ ID NO: 101 DNA

Homo sapiens HERV-K env >orico HERV K ENV codon optimized

MNPSEMQRKAPPRRRRHRNRAPLTHKMNKMVTSEEQMKLPSTKKAEPPTWAQLKKLT QL

ATKYLENTKVTQTPESMLLAA

LMIVSMVVSLPMPAGAAAANYTYWAYVPFPPLIRAVTWMDNPIEVYVNDSVWVPGPT DDRC

PAKPEEEGMMINISIGYRY

PPICLGRAPGCLMPAVQNWLVEVPTVSPISRFTYHMVSGMSLRPRVNYLQDFSYQRS LKFR

PKGKPCPKEIPKESKNTEV

LVWEECVANSAVILQNNEFGTIIDWAPRGQFYHNCSGQTQSCPSAQVSPAVDSDLTE SLDK

HKHKKLQSFYPWEWGEKGI

STPRPKIISPVSGPEHPELWRLTVASHHIRIWSGNQTLETRDRKPFYTIDLNSSLTV PLQSCV

KPPYMLVVGNIVIKPDS

QTITCENCRLLTCIDSTFNWQHRILLVRAREGVWIPVSMDRPWEASPSVHILTEVLK GVLNR

SKRFIFTLIAVIMGLIAV

TATAAVAGVALHSSVQSVNFVNDWQKNSTRLWNSQSSIDQKLANQINDLRQTVIWMG DRL

MSLEHRFQLQCDWNTSDFCI

TPQIYNESEHHWDMVRRHLQGREDNLTLDISKLKEQIFEASKAHLNLVPGTEAIAGV ADGLA N LN PVTWVKTI GSTTI I N

LILILVCLFCLLLVCRCTQQLRRDSDHRERAMMTMVVLSKRKGGNVGKSKRDQIVTV SV

SEQ ID NO: 102 DNA

Homo sapiens HERV-K env K10

>AAD51800.1

MNPSEMQRKAPPRRRRHRNRAPLTHKMNKMVTSEEQMKLPSTKKAEPPTWAQLKKLT QL

ATKYLENTKVTQTPESMLLAA

LMIVSMVVSLPMPAGAAAANYTNWAYVPFPPLIRAVTWMDNPIEVYVNDSVWVPGPI DDRC

PAKPEEEGMMINISIGYRY

PICLGRAPGCLMPAVQNWLVEVPIVSPICRFTYHMVSGMSLRPRVNYLQDFSYQRSL KFRP KGKPCPKEI PKESKNTEVL

VWEECVANSAVILQNNEFGTIIDWTPQGQFYHNCSGQTQSCPSAQVSPAVDSDLTES LDKH

KHKKLQSFYPWEWGEKGIS

TPRPKIISPVSGPEHPELWRLTVASHHIRIWSGNQTLETRDRKPFYTVDLNSSLTLP LQSCVK

PPYMLVVGNIVIKPDSQ

TITCENCRLLTCIDSTFNWQHRILLVRAREGVWIPVSMDRPWEASPSIHILTEVLKG VLNRSK

RFIFTLIAVIMGLIAVT

ATAAVAGVALHSSVQSVNFVNDGQKNSTRLWNSQSSIDQKLANQINDLRQTVIWMGD RLM

SLEHRFQLQCDWNTSDFCIT

PQIYNESEHHWDMVRRHLQGREDNLTLDISKLKEQIFEASKAHLNLVPGTEAIAGVA DGLAN LN PVTWVKTI GSTTI I N L

ILILVCLFCLLLVCRCTQQLRRDSDHRERAMMTMAVLSKRKGGNVGKSKRDQIVTVS V

SEQ ID NO: 103 DNA

Homo sapiens HERV-K env-2 >AAZ91341.1

MVTPVTWMDNPIEVYVNDSVRVPGPTDDRCPIKPEEEGIMINISTGYRYPICLGRAP GCLIHA

VQNWLVEVPTVSPNGRF

TYHMVSGMSLRPRVNYLQDFSYQRSLKFRPKGKPCPKEIPKESKNTEVLVWEECVAN SAVI

LQNNEFGTIIDWAPRGQFD

HNCSGQTQLCPSAQVSPAVDSDLTESLDKHKHKKLQSLYPWEWGEKGISTPRPKIIS PVSG

PEHPELWRLIVASHHIRIW SGNQTSETRDRKPFYTIDLNSSLTVPLQSCVKPPYMLVVGNIVIKPDSQTITCENCRLFT CIDS TFN WQQRI LLVRAREG

VWIPVSMDRPWEASPSIHILTEVLKGILNRSKRFIFTLIAVIMGLIAVTATAAVAGV ALHSSVQS

VNFVNDWQKNSARLW

NSQSSIDQKLANQINHLRQTHLDRRQTHELRTSFPVTV

SEQ ID NO: 104 DNA

Homo sapiens HERV-K env >AAY87455.1 ynepirdakkrastemvtpvtwmdnpievyvndsewvpgptddrcpakpeeegtmlnisi gyryppiclgtapgclmpav qnwlvevpivspisrftyhmvsgmslrprvnylqdfpyqrslkfrpkgkpcpkeipkesk nteilvweecvansavilqn nefgtiidwaprgqfyhncsgqtqscpsaqvspavdsdltesldkhkhkklqsfypwewg ekgistprpkiispvsgpeh pelwrltvashhiriwsgnqtletrdrkpfytvdlnssltlplqscvkppymlvvgnivi kpdsqtitcencrlltcids tfnwqhrillvraregvwilvsmdrpweaspsvhiltevlkgvlnrskrfiftliavi gliavtatgavagvalhssvq svnfvndwqknstrlwnsqssidqklanqindlrqtviwmgdrlmslehrfqlqcdwnts dfcitpqiynesehhwdmvr hhlqgrednltldisklkeqifeaskahlnlvpgteaiagvadglanlnpvtwvktigst tiinlililvclfclllvcr ctqqlrrdsdhrerammtmtvlskrkggnvgkskrdqivtvsv

SEQ ID NO: 105 DNA

Homo sapiens HERV-K env K108 >069384

MNPSEMQRKAPPRRRRHRNRAPLTHKMNKMVTSEEQMKLPSTKKAEPPTWAQLKKLT QL

ATKYLENTKVTQTPESMLLAA

LMIVSMVVSLPMPAGAAAANYTYWAYVPFPPLIRAVTWMDNPTEVYVNDSVWVPGPI DDRC

PAKPEEEGMMINISIGYHY

PPICLGRAPGCLMPAVQNWLVEVPTVSPICRFTYHMVSGMSLRPRVNYLQDFSYQRS LKFR

PKGKPCPKEIPKESKNTEV

LVWEECVANSAVILQNNEFGTIIDWAPRGQFYHNCSGQTQSCPSAQVSPAVDSDLTE SLDK

HKHKKLQSFYPWEWGEKGI

STPRPKIVSPVSGPEHPELWRLTVASHHIRIWSGNQTLETRDRKPFYTIDLNSSLTV PLQSCV

KPPYMLVVGNIVIKPDS

QTITCENCRLLTCIDSTFNWQHRILLVRAREGVWIPVSMDRPWEASPSVHILTEVLK GVLNR

SKRFIFTLIAVIMGLIAV

TATAAVAGVALHSSVQSVNFVNDWQKNSTRLWNSQSSIDQKLANQINDLRQTVIWMG DRL

MSLEHRFQLQCDWNTSDFCI

TPQIYNESEHHWDMVRRHLQGREDNLTLDISKLKEQIFEASKAHLNLVPGTEAIAGV ADGLA N LN PVTWVKTI GSTTI I N

LILILVCLFCLLLVCRCTQQLRRDSDHRERAMMTMAVLSKRKGGNVGKSKRDQIVTV SV

SEQ ID NO: 106 DNA

Homo sapiens HERV-K env k113

>AAD21098.1

MNPSEMQRKAPPRRRRHRNRAPLTHKMNKMVTSEEQMKLPSTKKAEPPTWAQLKKLT QL

ATKYLENTKVTQTPESMLLAA

LMIVSMVVSLPMPAGAAAANYTYWAYVPFPPLIRAVTWMDNPTEVYVNDSVWVPGPI DDRC

PAKPEEEGMMINISIGYHY PPICLGRAPGCLMPAVQNWLVEVPTVSPICRFTYHMVSGMSLRPRVNYLQDFSYQRSLKF R

PKGKPCPKEIPKESKNTEV

LVWEECVANSAVILQNNEFGTIIDWAPRGQFYHNCSGQTQSCPSAQVSPAVDSDLTE SLDK

HKHKKLQSFYPWEWGEKGI

STPRPKIVSPVSGPEHPELWRLTVASHHIRIWSGNQTLETRDRKPFYTIDLNSSLTV PLQSCV

KPPYMLVVGNIVIKPDS

QTITCENCRLLTCIDSTFNWQHRILLVRAREGVWIPVSMDRPWEASPSVHILTEVLK GVLNR

SKRFIFTLIAVIMGLIAV

TATAAVAGVALHSSVQSVNFVNDWQKNSTRLWNSQSSIDQKLANQINDLRQTVIWMG DRL

MSLEHRFQLQCDWNTSDFCI

TPQIYNESEHHWDMVRRHLQGREDNLTLDISKLKEQIFEASKAHLNLVPGTEAIAGV ADGLA N LN PVTWVKTI GSTTI I N

LILILVCLFCLLLVCRCTQQLRRDSDHRERAMMTMAVLSKRKGGNVGKSKRDQIVTV SV

SEQ ID NO: 107

DNA

Homo sapiens HERV-K env ERVK6 >AAF88168.1

MNPSEMQRKAPPRRRRHRNRAPLTHKMNKMVTSEEQMKLPSTKKAEPPTWAQLKKLT QL

ATKYLENTKVTQTPESMLLAA

LMIVSMVVSLPMPAGAAAANYTYWAYVPFPPLIRAVTWMDNPTEVYVNDSVWVPGPI DDRC

PAKPEEEGMMINISIGYHY

PPICLGRAPGCLMPAVQNWLVEVPTVSPICRFTYHMVSGMSLRPRVNYLQDFSYQRS LKFR

PKGKPCPKEIPKESKNTEV

LVWEECVANSAVILQNNEFGTIIDWAPRGQFYHNCSGQTQSCPSAQVSPAVDSDLTE SLDK

HKHKKLQSFYPWEWGEKGI

STPRPKIVSPVSGPEHPELWRLTVASHHIRIWSGNQTLETRDRKPFYTIDLNSSLTV PLQSCV

KPPYMLVVGNIVIKPDS

QTITCENCRLLTCIDSTFNWQHRILLVRAREGVWIPVSMDRPWEASPSVHILTEVLK GVLNR

SKRFIFTLIAVIMGLIAV

TATAAVAGVALHSSVQSVNFVNDWQKNSTRLWNSQSSIDQKLANQINDLRQTVIWMG DRL

MSLEHRFQLQCDWNTSDFCI

TPQIYNESEHHWDMVRRHLQGREDNLTLDISKLKEQIFEASKAHLNLVPGTEAIAGV ADGLA NLN PVTWVKTI GSTTI IN

LILILVCLFCLLLVCRCTQQLRRDSDHRERAMMTMAVLSKRKGGNVGKSKRDQIVTV SV

SEQ ID NO: 108 DNA

Homo sapiens HERV-K env k113

>AAD51798.1

MNPSEMQRKAPPRRRRHRNRAPLTHKMNKMVTSEEQMKLPSTKKAEPPTWAQLKKLT QL

ATKYLENTKVTQTPESMLLAA

LMIVSMVVSLPMPAGAAAANYTYWAYVPFPPLIRAVTWMDNPTEVYVNDSVWVPGPI DDRC

PAKPEEEGMMINISIGYHY

PPICLGRAPGCLMPAVQNWLVEVPTVSPICRFTYHMVSGMSLRPRVNYLQDFSYQRS LKFR

PKGKPCPKEIPKESKNTEV

LVWEECVANSAVILQNNEFGTIIDWAPRGQFYHNCSGQTQSCPSAQVSPAVDSDLTE SLDK

HKHKKLQSFYPWEWGEKGI

STPRPKIVSPVSGPEHPELWRLTVASHHIRIWSGNQTLETRDRKPFYTIDLNSSLTV PLQSCV

KPPYMLVVGNIVIKPDS

QTITCENCRLLTCIDSTFNWQHRILLVRAREGVWIPVSMDRPWEASPSVHILTEVLK GVLNR

SKRFIFTLIAVIMGLIAV TATAAVAGVALHSSVQSVNFVNDWQKNSTRLWNSQSSIDQKLANQINDLRQTVIWMGDRL

MSLEHRFQLQCDWNTSDFCI

TPQIYNESEHHWDMVRRHLQGREDNLTLDISKLKEQIFEASKAHLNLVPGTEAIAGV ADGLA N LN PVTWVKTI GSTTI I N

LILILVCLFCLLLVCRCTQQLRRDSDHRERAMMTMAVLSKRKGGNVGKSKRDQIVTV SV

SEQ ID NO: 109 DNA

Homo sapiens HERV-K env >BAB11758.1

MDNPIEVYVNDSVWVPGPTDDRCPAKPEEERMMINISIGYRYPPICLGRAPGCLMPA VQNW

LVEVPTVSPISRFTYHMVS

GMSLRPQVNYLQDFSYQRSLKFRPKRKPCLKEIPKESKNTEVLV

SEQ ID NO: 110 DNA

Homo sapiens HERV-K env >AAA88033.1 mgplqpglpspamipkdwpliiidlkdcfftiplaeqdcekfaftipainnkepatrfqw kvlpqgmlnspticqtfvgr alqpvrekfsdcyiihyiddilcaaetkdklidcytflqaevanaglaiasdkiqtstpf hylgmqienrkikpqkieir kdtlktlndfqkllgdinwirptlgiptyamsnlfsilrgdsdlnsqriltpeatkeikl veekiqsaqinridplaplq llifatahsptgiiiqntdlvewsflphstvktftlyldqiatligqtrlritklcgndp dkivvpltkeqvrqafinsg awqiglanfvglidnhypktkifqflklttwilpkitrreplenaltvftdgssngkaay tgpkerviktpyqsaqrdel vavitvlqdfdqpiniisdsayvvqatrdvetalikysmddqlnqlfnllqqtvrkrnfp fyityirahtnlpgpltkan eqadllvssalikaqelhalthvnaaglknkfdvtwkqakdivqhctqcqvlhlptqeag vnprglcpnalwqmdvthvp sfgrlsyvhvtvdtyshfiwatcqtgestshvkkhllscfavmgvpekiktdngpgycsk afqkflsqwkishttgipyn sqgqaivertnrtlktqlvkqkeggdskecttpqmqlnlalytlnflniyrnqtttsaeq hltgkknsphegkliwwkdn knktweigkvitwgrgfacvspgenqlpvwlptrhlkfynepigdakkrastemvtpvtw mdnpievyvndsiwvpgpid drcpakpeeegmminisigyryppiclgrapgclmpavqnwlvevptvspisrftyhmvs gmslrprvnylqdfsyqrsl kfrpkgkpcpkeipkeskntevlvweecvansavilnnefgtiidwaprgqfyhncsgqt qscpsaqvspavdsdltesl dkhkhkklqsfypwewgekgistprpkivspvsgpehpelwrltvashhiriwsgnqtle trdckpfytvdlnssltvpl qscvkppymlvvgnivikpdsqtitcencrlltcidstfnwqhrillvraregvwipvsm drpweaspsvhiltevlkgv

Inrskrfiftliavimgliavtataavagvalhssvqsvnfvndwqknstrlwnsqs sidqklanqindlrqtviwmgdr

Imslehrfqlqcdwntsdfcitpqiynesehhwdmvrrhlqgrednltldisklkeq ifeaskahlnlvpgteaiagvad glanlnpvtwvktigstsiinlililvclfclllvcrctqqlrrdsdhrerammtmavls krkggnvgkskrdqivtvsv

SEQ ID NO: 111 DNA

Homo sapiens HERV-K env >BAB11760.1

MVTPVTWMDNPIEVYVNDSVWVPGPTDDRCPAKPEEEGMMINISIVYRYPPICLGRA PGCL

MPAVQNWLVEVPTVSPNSR

FTYHMVSGMSLRPRVNYLQDFSYQRSLKFRPKGKPCPKEIPKESKNTEVLVWEECVA NSAV

ILQNNEFGTIIDWAPRGQF

YHNCSGQTQSCPSAQVSPAVDSDLTESLDKHKH KKLQSFYPWEWGEKGISTPRPEIISPVS

GPEHPELWRLWPDTTLEFG

LEIKL

SEQ ID NO: 112 DNA

Homo sapiens HERV-K env >BAB11759.1

MGQTKSKTKSKYASYLSFI Kl LLKRGGVRVSTKN LI KLFQII EQFCPWFPEQGTLDLKDWKRIG EELKQAGRKGNIIPLT

VWNDWAIIKAALEPFQTKEDSVSVSDAPGSCVIDCNEKTGRKSQKETESLHCEYVTE PVMA

QSTQNVDYNQLQGVIYPET

LKLEGKGPELVGPSESKPRGPSPLPAGQVPVTLQPQTQVKENKTQPPVAYQYWPPAE LQY

LPPPESQYGYPGMPPALQGR

APYPQPPTVRLNPTASRSGQGGTLHAVIDEARKQGDLEAWRFLVILQLVQAGEETQV GAPA

RAETRCEPFTMKMLKDIKE

GVKQYGSNSPYIRTLLDSIAHGNRLTPYDWESLAKSSLSSSQYLQFKTWWIDGVQEQ VRKN QATKPTVN I DA DQ LLGT G P

NWSTINQQSVMQNEAIEQVRAICLRAWGKIQDPGTAFPINSIRQGSKEPYPDFVARL QDAAQ

KSITDDNARKVIVELMAY

ENANPECQSAIKPLKGKVPAGVDVITEYVKACDGIGGAMHKAMLMAQAMRGLTLGGQ VRTF

GKKCYNCGQIGHLKRSCPV

LNKQNIINQAITAKNKKPSGLCPKCGKGKHWANQCHSKFDKDGQPLSGNRKRGQPQA PQQ

TGAFPVQLFVPQGFQGQQPL

QKI PPLQGVSQLQQSNSCPAPQQAAPQ

SEQ ID NO: 113 DNA

Homo sapiens HERV-K env >HERV-K113 mnpsemqrkapprrrrhrnraplthkmnkmvtseeqmklpstkkaepptwaqlkkltqla tkylentkvtqtpesmllaa

Imivsmvvslpmpagaaaanytywayvpfppliravtwmdnpieiyvndsvwvpgpt ddccpakpeeegmminisigyry ppiclgrapgclmpavqnwlvevptvspisrftyhmvsgmslrprvnylqdfsyqrslkf rpkgkpcpkeipkeskntev

Ivweecvansavilqnnefgtlidwaprgqfyhncsgqtqscpsaqvspavdsdlte sldkhkhkklqsfypwewgekgi starpkiispvsgpehpelwrltvashhiriwsgnqtletrdrkpfytidlnssltvplq scvkppymlvvgnivikpds qtitcencrlltcidstfnwqhrillvraregvwipvsmdrpweaspsvhiltevlkgvl nrskrfiftliavimgliav tataavagvalhssvqsvnfvndwqnnstrlwnsqssidqklanqindlrqtviwmgdrl mslehrfqlqcdwntsdfci tpqiynesehhwdmvrchlqgrednltldisklkeqifeaskahlnlvpgteaiagvadg lanlntvtwvktigsttiin lililvclfclllvyrctqqlrrdsdhrerammtmvvlskrkggnvgkskrdqivtvsv

SEQ ID NO: 114 DNA

Homo sapiens HERV-K env >DQ112146.1

MVTPVTWMDNPIEIYVNDSVWVPGPIDDRCPAKPEEEGMMINISIGYRYPPICLGRA PGCLM

PAVQNWLVEVPTVSPISRFTYHMVSGMSLRPRVNYLQDFSYQRSLKFRPKGKPCPKE IPKE

SKNTEVLVWEECVANSAVILQNNEFGTIIDWAPRGQFYHNCSGQTQSCPSAQVSPAV DSDL

TESLDKHKHKKLQSFYPWEWGEKGISTPRPKIVSPVSGPEHPELWRLTVASHHIRIW SGNQ

TLETRDCKPFYTIDLNSSLTVPLQSCVKPPYMLVVGNIVIKPDSQTITCENCRLLTC IDSTFNW

QHRILLVRAREGVWIPVSMDRPWEASPSVHILTEVLKGVLNRSKRFIFTLIAVIMGL IAVTATA

AVAGVALHSSVQSVNFVNDWQKNSTRLWNSQSSIDQKLANQINDLRQTVIWMGDRLM SLE

HRFQLQCDWNTSDFCITPQIYNESEHHWDMVRRHLQGREDNLTLDISKLKEQIFEAS KAHL

NLVPGTEAIAGVADGLANLNPVTWVKTIGSTTIINLILILVCLFCLLLVCRCTQQLR RDSDHRE

RAMMTMAVLSKRKGGNVGKSKR

SEQ ID NO: 115 DNA

Homo sapiens HERV-K env >CAA63481.1 MNPSEMQRKAPPRRRRHRNRAPLTHKMNKMVTSEEQMKLPSTKK

AEPPTWAQLKKLTQLATKYLENTKVTQTPESMLLAALMIVSMVVSLPMPAGAAAANY T

YWAYVPFPPLIRAVTWMDNPIEVYVNDSVWVPGPTDDHCPAKPEEEGMMINISIGYR Y

PPICLGRAPGCLMPAVQNWLVEVPTVSPISRFTYHMVSGMSLRPRVNYLQDFSYQRS F

KFRPKGKPCPKEIPKESKNTEVLVWEECVANSAVILQNNEFGTIIDWAPRGQFYHNC S

GQTQSCPSAQVSPAVDSDLTESLDKH KHKKLQSFYPWEWGEKGISTPRPKIISPVSGP

EHPELWRLTVASHHIRIWSGNQTLETRDRKPFYTVDLNSSVTVPLQSCIKPPYMLVV G

NIVIKPDSQTITCENCRLLTCIDSTFNWQHRILLVRAREGVWIPVSMDRPWETSPSI H

TLTEVLKGVLNRSKRFIFTLIAVIMGLIAVTATAAVAGVALHSSVQSVNFVNDWQKN S

TRLWNS

SEQ ID NO: 116 DNA

Homo sapiens HERV-K env >Q902F9

MNPSEMQRKAPPRRRRHRNRAPLTHKMNKMVTSEEQMKLPSTKKAEPPTWAQLKKLT QL

ATKYLENTKVTQTPESMLLAA

LMIVSMVVSLPMPAGAAAANYTYWAYVPFPPLIRAVTWMDNPIEIYVNDSVWVPGPT DDCC

PAKPEEEGMMINISIGYRY

PPICLGRAPGCLMPAVQNWLVEVPTVSPISRFTYHMVSGMSLRPRVNYLQDFSYQRS LKFR

PKGKPCPKEIPKESKNTEV

LVWEECVANSAVILQNNEFGTLIDWAPRGQFYHNCSGQTQSCPSAQVSPAVDSDLTE SLDK

HKHKKLQSFYPWEWGEKGI

STARPKIISPVSGPEHPELWRLTVASHHIRIWSGNQTLETRDRKPFYTIDLNSSLTV PLQSCV

KPPYMLVVGNIVIKPDS

QTITCENCRLLTCIDSTFNWQHRILLVRAREGVWIPVSMDRPWEASPSVHILTEVLK GVLNR

SKRFIFTLIAVIMGLIAV

TATAAVAGVALHSSVQSVNFVNDWQNNSTRLWNSQSSIDQKLANQINDLRQTVIWMG DRL

MSLEHRFQLQCDWNTSDFCI

TPQIYNESEHHWDMVRCHLQGREDNLTLDISKLKEQIFEASKAHLNLVPGTEAIAGV ADGLA N LNTVTWVKTIGSTTI I N

LILILVCLFCLLLVYRCTQQLRRDSDHRERAMMTMVVLSKRKGGNVGKSKRDQIVTV SV

SEQ ID NO: 117 DNA

Homo sapiens HERV-K env >Q902F8

MNPSEMQRKAPPRRRRHRNRAPLTHKMNKMVTSEEQMKLPSTKKAEPPTWAQLKKLT QL

ATKYLENTKVTQTPESMLLAA

LMIVSMVVSLPMPAGAAVANYTNWAYVPFPPLIRAVTWMDNPIEVYVNDSVWVPGPI DDRC

PAKPEEEGMMINISIGYRY

PPICLGRAPGCLMPAVQNWLVEVPTVSPISRFTYHMVSGMSLRPRVNYLQDFSYQRS LKFR

PKGKPCPKEIPKESKNTEV

LVWEECVANSAVILQNNEFGTIIDWAPRGQFYHNCSGQTQSCPSAQVSPAVDSDLTE SLDK H KH KKLQSFYPWEWG EKRI

STPRPKIVSPVSGPEHPELWRLTVASHHIRIWSGNQTLETRDRKPFYTVDLNSSLTL PLQSC

VKPPYMLVVGNIVIKPDS

QTITCENCRLLTCIDSTFNWQHRILLVRAREGVWIPVSMDRPWEASPSVHILTEVLK GVLNR

SKRFIFTLIAVIMGLIAV

TATAAVAGVALHSSVQSVNFVNDGQKNSTRLWNSQSSIDQKLANQINDLRQTVIWMG DRL

MSLEHRFQLQCDWNTSDFCI

TPQIYNDSEHHWDMVRRHLQGREDNLTLDISKLKEQIFEASKAHLNLVPGTEAIAGV ADGLA N LN PVTWVKTI GSTTI I N LILILVCLFCLLLVCRCTQQLRRDSDHRERAMMTMAVLSKRKGGNVGKSKRDQIVTVSV

SEQ ID NO: 118 DNA

Homo sapiens HERV-K env >Q9QC07

NKSRKRRNRVSFLGVTTVEPPKPIPLTWKTEKLVWVNQWPLPKQKLEALHLLANEQL EKGHI

EPSFSPWNSPVFVIQKKS

SKWRMLTDLRAVNAVIQPMGPLQPGLPSPAMIPKDWPLIIIDLKDCFFTIPLAEQDC EKFAFTI

PAINNKEPATRFQWKV

LPQGM LNSPTICQTFVGRALQPVRDKFSDCYI I HYFDDI LCAAETKDKLI DCYTFLQAEVANA GLAIASDKIQTSTPFHY

LGMQIENRKI KPQKIEIRKDTLKTLNDFQKLLGDINWIRPTLGIPTYAMSNLFSILRGDSDLNSK RMLTPEATKEIKLVE

EKIQSAQINRIDPLAPLQLLIFATAHSPTGIIIQNTDLVEWSFLPHSTVKTFTLYLD QIATLIGPTR

LRIIKLCGNDPDK

IVVPLTKEQVRQAFINSGAWQIGLANFVGIIDNHYPKTKIFQFLKLTTWILPKITRR EPLENALT

VFTDGSSNGKVAYTG

PKERVIKTPYQSAQRAELVAVITVLQDFDQPINIISDSAYVVQATRDVETALIKYSM DDQLNQL

FNLLQQTVRKRNFPFY

ITHIRAHTNLPGPLTKANEQADLLVSSAFIKAQELHALTHVNAAGLKNKFDVTWKQA KDIVQH

CTQCQVLDLPTQEAGVN

PEVCVLMHYGKWMSHMYLHLGRLSYVHVTVDTYSHFMCATCQTGESTSHVKKHLLSC FAV

MGVPEKIKTDNGPGYCSKAF

QKFLSQWKISHTTGIPYNSQGQAIVERTNRTLKTQLVKQKEGGDSKECTTPQMQLNL ALYTL

NFLNIYRNQTTTSAEHLT

GKKNSPHEGKLI

SEQ ID NO: 119 DNA

Homo sapiens HERV-K env >Q9NX77

MWTVPSFTNDSYQVYNVFSTNSFQLLTVKRTPHEAWRVPLTTKTNKTKGLPDCPKKP TNG PFIVTSI LWDNCNAPKAVVL

QTLAMGIVIDWAPKGHYWQDCSSKNTLCSEFIYSLDYIEHGWQSYTMRQRVSPYPFK WMD

TGIAPPRPKIIHPFFTPEHP

ELWKLAAALSGIKIWNTTYQLLRTKTKTPTFNITLISEWVIPIRSCVKPPYMLLVGN IIMMPDAQ

TIECHNCKLFTCIDA

TFNPTTSILLVRAREGVWIPVSLHRPWESSPSIHIVNEVLKDILKRTKRFIFTLIAV LAGLLAVTA

TAATAGVAIRSSVQ

TAHYVEACQKNSSRLWNSQAQIDQKLANQINDLRQSVTWLGDRVMNLQHRMQLQCDW NT

SDYCITPYAYNQDQHSWENVS

RHLKAWDDNLTLDISQLKEQIFEASQAHLSTVPGSHIFEGITKQLPDFNPFKWLKPV RGSLLL LALLI LVCLCCLLLVCR CL

SEQ ID NO: 120 DNA

Homo sapiens HERV-K env >Q9HDB8

MVTPVTWMDNPIEVYVNDSVWVPGPTDDRCPAKPEEEGMMINISIVYRYPPICLGRA PGCL

MPAVQNWLVEVPTVSPNSR FTYHMVSGMSLRPRVNYLQDFSYQRSLKFRPKGKPCPKEIPKESKNTEVLVWEECVANSA V

ILQNNEFGTIIDWAPRGQF

YHNCSGQTQSCPSAQVSPAVDSDLTESLDKHKH KKLQSFYPWEWGEKGISTPRPEIISPVS

GPEHPELWRLWPDTTLEFG

LEIKL

SEQ ID NO: 121 DNA

Homo sapiens HERV-K env >P63123

WASQVSENRPVCKAVIQGKQLEGLVDTGADVSIIALNQWPKNWPKQKTVTGLVGIVT ASEV

YQSTEILHCLGPHNQESTV

QPMITSIPLNLWGRDLLQQWGAEITMTATLYSPMSQKIMTKMGYIPGKGLGKNEDGI KVPIEA

KINHGREGTGYPF

SEQ ID NO: 122 DNA

Homo sapiens HERV-K env >P61570

MNPSEMQRKAPPRRRRHRNRAPLTHKMNKMVTSEEQMKLPSTKKAEPPTWAQLKKLT QL

ATKYLENTKVTQTPESMLLAA

LM I VSM VVSLPM PAGAAAANYTYWAYVPFPPLI RAVTWMDN PI EVYVN DSVWVPGPI DDRC PAKPEEEGMMINISIGYRY

PPICLGTAPGCLMPAVQNWLVEVPIVSPISRFTYHMVSGMSLRPRVNYLQDFSYQRS LKFR

PKGKPCPKEIPKESKNTEV

LVWEECVANSAVILQNNEFGTIIDWAPRGQFYHNCSGQTQSCPSAQVSPAVDSDLTE SLDK

HKHKKLQSFYPWEWGEKGI

STPRPKIVSPVSGPEHPELWRLTVASHHIRIWSGNQTLETRDRKPFYTVDLNSSLTV PLQSC

VKPPYMLVVGNIVIKPDS

QTITCENCRLLTCIDSTFNWQHRILLVRAREGVWIPVSMDRPWEASPSIHILTEVLK GVLNRS

KRFIFTLIAVIMGLIAV

TATGAVAGVALHSSVQSVNFVNDWQKNSTRLWNSQSSIDQKLANQINDLRQTVIWMG DRL

MSLEHRFQLQCDWNTSDFCI

TPQIYNESEHHWDMVRRHLQGREDNLTLDISKLKEQIFKASKAHLNLVPGTEAIAGV ADGLA

N LN PVTWVKTI GSTTI I N

LILILVCLFCLLLVCRCTQQL

SEQ ID NO: 123 DNA

Homo sapiens HERV-K env >P61568

MPGAIDDHCPAQPGEEGTAFNVTMGYKYPPLCLGHATRCIHLETQVWAAYLLERLAT GKW

GHLVSGLSLCPLRQMKRGVI

GDTPYFQYKPVGKLCPKNFEGPSKTLIWGDCVNSHAVVLKNDSYALVIDWAPKGYLK NTCS

SGGGEFLEATYFISYWEDE

DHHPTLHRWFGSFFTLKWEDKDITLHPQGLV

SEQ ID NO: 124 DNA

Homo sapiens HERV-K env >P61567 MVTPVTWMDNPIEIYVNDSVWVPGPIDDRCPAKPEEEGMMINISIGYRYPPICLGRAPGC LM

PAVQNWLVEVPTVSPISR

FTYHMVSGMSLRPRVNYLQDFSYQRSLKFRPKGKPCPKEIPKESKNTEVLVWEECVA NSAV

ILQNNEFGTIIDWAPRGQF

YHNCSGQTQSCPSAQVSPAVDSDLTESLDKHKHKKLQSFYPWEWGEKRISTPRPKIV SPVS

GPEHPELWRLTVASHHIRI

WSGNQTLETRDCKPFYTIDLNSSLTVPLQSCVKPPYMLVVGNIVIKPDSQTITCENC RLLSCI

DSTFNWQHRILLVRARE

GVWIPVSMDRPWEASPSVHILTEVLKGVLNRSKRFIFTLIAVIMGLIAVTATAAVAG VALHSSV

QSVNFVNDWQKNSTRL

WNSQSSIDQKLANQINDLRQTVIWMGDRLMSLEHRFQLQCDWNTSDFCITPQIYNES EHHW

DMVRRHLQGREDNLTLDIS

KLKEQIFEASKAHLNLVPGTEAIAGVADGLANLNPVTWVKTIGSTTIINLILILVCL FCLLLVCRC

TQQLRRDSDHRERA

MMTMAVLSKRKGGNVGKSKRDQIVTVSV

SEQ ID NO: 125 DNA

Homo sapiens HERV-K env >P61566

MVTPVTWMDNPIEVYVNDSEWVPGPTDDRCPAKPEEEGMMINISIGYRYPPICLGTA PGCL

MPAVQNWLVEVPIVSPISR

FTYHMVSGMSLRPRVNYLQDFPYQRSLKFRPKGKPCPKEIPKESKNTEVLVWEECVA NSAV

ILQNNEFGTIIDWAPRGQF

YHNCSGQTQSCPSAQVSPAVDSDLTESLDKHKH KKLQSFYPWEWGEKGISTPRPKIISPVS GPEHPELWRLTVASHHIRI

WSGNQTLETRDRKPFYTVDLNSSLTLPLQSCVKPPYMLVVGNIVIKPDSQTITCENC RLLTCI

DSTFNWQHRILLVRARE

GVWILVSMDRPWEASPSVHILTEVLKGVLNRSKRFIFTLIAVIMGLIAVTATGAVAG VALHSSV

QSVNFVNDWQKNSTRL

WNSQSSIDQKLANQINDLRQTVIWMGDRLMSLEHRFQLQCDWNTSDFCITPQIYNES EHHW

DMVRHHLQGREDNLTLDIS

KLKEQIFEASKAHLNLVPGTEAIAGVADGLANLNPVTWVKTIGSTTIINLILILVCL FCLLLVCRC

TQQLRRDSDHRERA

MMTMAVLSKRKGGNVGKSKRDQIVTVSV

SEQ ID NO: 126 DNA

Homo sapiens HERV-K env >P61565

MHPSEMQRKAPPRRRRHRNRAPLTHKMNKMVTSEQMKLPSTKKAEPPTWAQLKKLTQ LA

TKYLENTKVTQTPESMLLAAL

MIVSMVVSLPMPAGAAAANYTNWAYVPFPPLIRAVTWMDNPIEVYVNDSVWVHGPID DRCP

AKPEEEGMMINISIGYHYP

PICLGRAPGCLMPAVQNWLVEVPTVSPISRFTYNMVSGMSLRPRVNYLQDFSYQRSL KFRP

KGKPCPKEIPKESKNTEVL

VWEECVANSVVILQNNEFGTIIDWAPRGQFYHNCSGQTQSCPSAQVSPAVDSDLTES LDKH

KHKKLQSFYPWEWGEKGIS

TPRPKIISPVSGPEHPELWRLTVASHHIRIWSGNQTLETRDRKPFYTVDLNSSLTVP LQSCVK

PPYMLVVGNIVIKPDSQ

TITCENCRLLTCIDSTFNWQHRILLVRAREGVWIPVSMDRPWEASPSIHILTEVLKG VLNRSK

RFIFTLIAVIMGLIAVT AMAAVAGVALHSFVQSVNFVNDWQKNSTRLWNSQSSIDQKLANQINDLRQTVIWMGDRLM

SLEHRFQLQCDWNTSDFCIT

PQIYNESEHHWDMVRRHLQGREDNLTLDISKLKEQIFEASKAHLNLVPGTEAIAGVA DGLAN LN PVTWVKTI GSTTI I N L

ILILVCLFCLLLVCRCTQQLRRDSDHRERAMMTMVVLSKRKGGNVGKSKRDQIVTVS V

SEQ ID NO: 127 DNA

Homo sapiens HERV-K env >071037

MNPSEMQRKAPPRRRRHRNRAPLTHKMNKMVTSEEQMKLPSTKKAEPPTWAQLKKLT QL

ATKYLENTKVTQTPESMLLAA

LMIVSMVVSLPMPAGAAAANYTYWAYVPFPPLIRAVTWMDNPIEVYVNDSVWVPGPT DDHC

PAKPEEEGMMINISIGYRY

PPICLGRAPGCLMPAVQNWLVEVPTVSPISRFTYHMVSGMSLRPRVNYLQDFSYQRS FKFR

PKGKPCPKEIPKESKNTEV

LVWEECVANSAVILQNNEFGTIIDWAPRGQFYHNCSGQTQSCPSAQVSPAVDSDLTE SLDK

HKHKKLQSFYPWEWGEKGI

STPRPKIISPVSGPEHPELWRLTVASHHIRIWSGNQTLETRDRKPFYTVDLNSSVTV PLQSCI

KPPYMLVVGNIVIKPDS

QTITCENCRLLTCIDSTFNWQHRILLVRAREGVWIPVSMDRPWETSPSIHTLTEVLK GVLNRS

KRFIFTLIAVIMGLIAV

TATAAVAGVALHSSVQSVNFVNDWQKNSTRLWNSQSSIDQKLANQINDLRQTVIWMG DRL

MSLEHRFQLQCDWNTSDFSI

TPQIYNESEHHWDMVRRHLQGREDNLTLDISKLKEQIFEASKAHLNLVPGTEAIAGV ADGLA NLN PVTWVKTI GSTTI IN

LILILVCLFCLLLVCRCTQQLRRDSDHRERAMMTMAVLSKRKGGNVGKSKRDQIVTV SV

SEQ ID NO: 128 DNA

Homo sapiens HERV-K env >042043

MVTPVTWMDNPIEVYVNDSVWVPGPTDDRCPAKPEEEGMMINISIGYHYPPICLGRA PGCL

MPAVQNWLVEVPTVSPNSR

FTYHMVSGMSLRPRVNCLQDFSYQRSLKFRPKGKTCPKEIPKGSKNTEVLVWEECVA NSV

VILQNNEFGTIIDWAPRGQF

YHNCSGQTQSCPSAQVSPAVDSDLTESLDKHKHKKLQSFYLWEWEEKGISTPRPKII SPVS

GPEHPELWRLTVASHHIRI

WSGNQTLETRYRKPFYTIDLNSILTVPLQSCVKPPYMLVVGNIVIKPASQTITCENC RLFTCID

STFNWQHRILLVRARE

GMWIPVSTDRPWEASPSIHILTEILKGVLNRSKRFIFTLIAVIMGLIAVTATAAVAG VALHSSVQ

SVNFVNYWQKNSTRL

WNSQSSIDQKLASQINDLRQTVIWMGDRLMTLEHHFQLQCDWNTSDFCITPQIYNES EHHW

DMVRRHLQGREDNLTLDIS

KLKEQIFEASKAHLNLVPGTEAIAGVADGLANLNPVTWIKTIRSTMIINLILIVVCL FCLLLVCRC

TQQLRRDSDIENGP

SEQ ID NO: 129 DNA

Homo sapiens

HERV-W Env and Multiple sceloris related virus HERV-W Env >Q9UQF0 MALPYHIFLFTVLLPSFTLTAPPPCRCMTSSSPYQEFLWRMQRPGNIDAPSYRSLSKGTP TF

TAHTHMPRNCYHSATLCM

HANTHYWTGKMINPSCPGGLGVTVCWTYFTQTGMSDGGGVQDQAREKHVKEVISQLT RV

HGTSSPYKGLDLSKLHETLRT

HTRLVSLFNTTLTGLHEVSAQNPTNCWICLPLNFRPYVSIPVPEQWNNFSTEINTTS VLVGPL

VSNLEITHTSNLTCVKF

SNTTYTTNSQCIRWVTPPTQIVCLPSGIFFVCGTSAYRCLNGSSESMCFLSFLVPPM TIYTEQ

DLYSYVISKPRNKRVPI

LPFVIGAGVLGALGTGIGGITTSTQFYYKLSQELNGDMERVADSLVTLQDQLNSLAA VVLQN

RRALDLLTAERGGTCLFL

GEECCYYVNQSGIVTEKVKEIRDRIQRRAEELRNTGPWGLLSQWMPWILPFLGPLAA IILLLL

FGPCIFNLLVNFVSSRI

EAVKLQMEPKMQSKTKIYRRPLDRPASPRSDVNDIKGTPPEEISAAQPLLRPNSAGS S

SEQ ID NO: 130 DNA

Homo sapiens HERV-W Env >AAK18189.1

MALPYHTFLFTVLLPPFALTAPPPCCCTTSSSPYQEFLWRTRLPGNIDAPSYRSLSK GNSTF

TAHTHMPRNCYNSATLCM

HANTHYWTGKMINPSCPGGLGATVCWTYFTHTSMSDGGGIQGQAREKQVKEAISQLT RGH

STPSPYKGLVLSKLHETLRT

HTRLVSLFNTTLTRLHEVSAQNPTNCWMCLPLHFRPYISIPVPEQWNNFSTEINTTS VLVGPL

VSNLEITHTSNLTCVKF

SNTIDTTSSQCIRWVTPPTRIVCLPSGIFFVCGTSAYHCLNGSSESMCFLSFLVPPM TIYTEQ

DLYNHVVPKPHNKRVPI

LPFVIRAGVLGRLGTGIGSITTSTQFYYKLSQEINGDMEQVTDSLVTLQDQLNSLAA VVLQNR

RALDLLTAKRGGTCLFL

GEERCYYVNQSRIVTEKVKEIRDRIQCRAEELQNTERWGLLSQWMPWTLPFLGPLAA IIFLLL

FGPCIFNFLVKFVSSRI

EAVKLQIVLQMEPQMQSMTKIYRGPLDRPARLCSDVNDIEVTPPEEISTAQPLLHSN SVGSS

SEQ ID NO: 131 DNA

Homo sapiens HERV-W Env >AAD14545.1

MALPYHIFLFTVVSPSFTLTAPPPCRCMTSSSPYQEFLWRMQRPGNIDAPSYRSLCK GTPTF

TAHTHMPRNCYHSATLCM

HANTHYWTGKMINPSCPGGLGVTVCWTYFTQTGMSDGGGVQDQAREKHVKEVISQLT RV

HGTSSPYKGLDLSKLHETLRT

HTRLVSLFNTTLTGLHEVSAQNPTNCWICLPLNFRPYVSIPVPEQWNNFSTEINTTS VLVGPL

VSNLEITHTSNLTCVKF

SNTTYTTNSQCIRWVTPPTQIVCLPSGIFFVCGTSAYRCLNGSSESMCFLSFLVPPM AIYTEQ

DLYSYVISKPRNKRVPI

LPFVIGAGVLGALGTGIGGITTSTQFYYKLSQELNGDMERVADSLVTLQDQLNSLAA VVLQN

RRALDLLTAERGGTCLFL

GEECCYYVNQ

SEQ ID NO: 132 DNA

Homo sapiens HERV-H Env >Q9N2J8 MILAGRAPSNTSTLMKFYSLLLYSLLFSFPFLYHPLPLPSYLHHTINLTHSLPAASNPSL ANNC

WLCISLSSSAYIAVPT

LQTDRATSPVSLHLRTSFNSPHLYPPEELIYFLDRSSKTSPDISHQPAAALLHIYLK NLSPYIN

STPPIFGPLTTQTTIP

VAAPLCISRQRPTGIPLGNISPSRCSFTLHLQSPTTHVTETIGVFQLHIIDKPSINT DKLKNVSS

NYCLGRHLPYISLHP

WLPSPCSSDSPPRPSSCLLTPSPQNNSERLLVDTQRFLIHHENRTSSSMQLAHQSPL QPLT

AAALAGSLGVWVQDTPFST

PSHPFSLHLQFCLTQGLFFLCGSSTYMCLPANWTGTCTLVFLTPKIQFANGTKELPV PLMTL

TPQKRVIPLIPLMVGLGL

SASTIALSTGIAGISTSVTTFRSPSNDFSASITDISQTLSVLQAQVDSLAAVVLQNR RGLGLSIL

LNEECCFYLNQSGLV

YENIKKLKDRAQKLANQASNYAESPWALSNWMSWVLPILSPLIPIFLLLLFGPCIFH LVSQFIQ

NRIQAITNHSI

SEQ ID NO: 133 DNA

Homo sapiens HERV-H Env >Q9N2K0

MIFAGKAPSNTSTLMKFYSLLLYSLLFSFPFLCHPLPLPSYLHHTINLTHSLLAASN PSLVNNC WLC I SLSSSAYT A VPA

VQTDWATSPISLHLRTSFNSPHLYPPEELIYFLDRSSKTSPDISHQQAAALLRTYLK NLSPYIN

STPPIFGPLTTQTTIP

VAAPLCISWQRPTGIPLGNLSPSRCSFTLHLRSPTTNINETIGAFQLHITDKPSINT DKLKNISS

NYCLGRHLPCISLHP

WLSSPCSSDSPPRPSSCLLIPSPENNSERLLVDTRRFLIHHENRTFPSTQLPHQSPL QPLTA

AALAGSLGVWVQDTPFST

PSHLFTLHLQFCLAQGLFFLCGSSTYMCLPANWTGTCTLVFLTPKIQFANGTEELPV PLMTP

TQQKRVIPLIPLMVGLGL

SASTVALGTGIAGISTSVMTFRSLSNDFSASITDISQTLSVLQAQVDSLAAVVLQNR RGLDLLT

AEKGGLCIFLNEECCF

YLNQSGLVYDNIKKLKDRAQKLANQASNYAEPPWALSNWMSWVLPIVSPLIPIFLLL LFGPCI

FRLVSQFIQNRIQAITN

HSIRQMFLLTSPQYHPLPQDLPSA

SEQ ID NO: 134 DNA

Homo sapiens HERV-H Env >CAB94193.2 mifagrassntstlmkfyslllysllfsfpilchplplpsylhhtinlthsllavsnpsl akncwlcislpssaypavpa

Iqtdwgtspvsphlrtsfnsphlyppekliyfldrssktspdishqqaaallctylk nlspyinstpptfgplttqttip vaaplcisrqrptgiplgnlspsrcsftlhlrsptthitetngafqlhitdkpsintdkl knvssnyclgrhlscislhp wlfspcssdspprpsscllipspknnsesllvdaqrfliyhenrtspstqlphqsplqpl taaplggslrvwvqdtpfst pshlftlhlqfclvqslfflcgsstymclpanwtgtctlvfltskiqfangteelpvplm tptrqkrvipliplmvglgl sastvalgtgiagistsvttfrilsndfsasitdisqtlsglqaqvdssaavvlqnrqgl dlltaekgglciflneesyf ylnqsglvydnikklkdkaqnlanqasnyaeppwplsnwmswvlpilsplipiflllffr pcifhlvsqfiqnhiqaitd his

SEQ ID NO: 135 DNA

Homo sapiens HERV-H Env >AAL11492.1 MIFAGKAPSNTSTLMKFYSLLLYSLLFSFPFLCHPLPLPSYLHHTVNLTHSLLAASNPSL ANN CWLC I S LSSSAYT A VP V

LQTDWATSPVSLHLRTSFNSPHLYPPEELIYFLDRSSKTSPDISHQQAAALLRTYLK NLSPYI NSTPPI FGPLTTQTTI P

VAAPLCISRQRPTGIPLGNLSPSRCSFTLHLRSPTTHITETIGAFQLHITDKPSINT DKLKNISS

NYCLGRHVPCISLHP

WLSSPCSSDSPPRPSSCLLIPSPENNSERLLVDTRRFLIHHENRTFPSTQLPHQSPL QPLTA

AALAGSLGVWVQDTPFST

PSHLFTLHLQFCLAQALFFLCGSSTYMCLPANWTGTCTLVFLTRKIQFANGTEELPV PLMTP

TQQKRVIPLIPLMVGLGL

SA

SEQ ID NO: 136 DNA

Homo sapiens HERV-H Env >AAL11491.1

MIFAGKAPSNTSTLMKFYSLLLYSLLFSFPFLCHPLPLPSYLHHTINLTHSLLAASN PSLVNNC WLC I SLSSSAYT A VPT

LQTDWATSPISLHLRTSCNSPHLYPPEELIYFLDRSSKTSPDISHQQAAALLRTYLK NLSPYIN STPPI FGPLTTQTTI P

VAAPLCISWQRPTGIPLGNLSPSRCSFTLHLRSPTTNINETIGAFQLHITDKPSINT DKLKNISS

NYCLGRHLPCISLHP

WLSSPCSSDSPPRPSSCLLIPSPENNSERLLVDTRRFLIHHENRTFPSTQLPHQSPL QPLTA

AALAGSLGVWVQDAPFST

PSHLFTLHLQFCLAQGLFFLCGSSTYMCLPANWTGTCTLVFLTPKIQFANGTEELPV PLMTP

TQQKRVIPLIPLMVGLGL

SA

SEQ ID NO: 137 DNA

Homo sapiens HERV-H Env >AAD34324.1

MIFAGKAPSNTSTLMKFYSLLLYSLLFSFPFLCHPLPLPSYLHHTINLTHSLLAASN PSLVNNC WLC I SLSSSAYT A VPA

LQTDWATSPISLHLRTSFNSPHLYPPEELIYFLDRSSKTSPDISHQQAAALLRTYLK NLSPYIN ST P P I LG P LTT QTT I P

VAAPLCISWQRPTGIPLGNLSPSRCSFTLHLRSPTTNINETIGAFQLHITDKPSINT DKLKNISS

NYCLGRHLPCISLHP

WLSSPCSSDSPPRPSSCLLIPSPENNSERLLVDTRRFLIHHENRTFPSTQLPHQSPL QPLTA

AALAGSLGVWVQDTPFST

PSHLFTLHLQFCLAQGLFFLCGSSTYMCLPANWTGTCTLVFLTPKIQFANGTEELPV PLMTP

TQQKRVIPLIPLMVGLGL

SASTVALGTGIAGISTSVMTFRSLSNDFSASITDISQTLSVLQAQVDSLAAVVLQNR RGLDLLT

AEKGGLCIFLNEECCF

YLNQSGLVYDNIKKLKDRAQKLANQASNYAEPPWALSNWMSWVLPIVSPLIPIFLLL LFGPCI

FRLVSQFIQNRIQAITN

HSIRQMFLLTSPQYHPLPQDLPSA

SEQ ID NO: 138 DNA

Homo sapiens HERV-R Env >Q 14264 MLGMNMLLITLFLLLPLSMLKGEPWEGCLHCTHTTWSGNIMTKTLLYHTYYECAGTCLGT CT

HNQTTYSVCDPGRGQPYV

CYDPKSSPGTWFEIHVGSKEGDLLNQTKVFPSGKDVVSLYFDVCQIVSMGSLFPVIF SSMEY

YSSCHKNRYAHPACSTDS

PVTTCWDCTTWSTNQQSLGPIMLTKIPLEPDCKTSTCNSVNLTILEPDQPIWTTGLK APLGA

RVSGEEIGPGAYVYLYII

KKTRTRSTQQFRVFESFYEHVNQKLPEPPPLASNLFAQLAENIASSLHVASCYVCGG MNMG

DQWPWEARELMPQDNFTLT

ASSLEPAPSSQSIWFLKTSIIGKFCIARWGKAFTDPVGELTCLGQQYYNETLGKTLW RGKSN

NSESPHPSPFSRFPSLNH

SWYQLEAPNTWQAPSGLYWICGPQAYRQLPAKWSGACVLGTIRPSFFLMPLKQGEAL GYP

IYDETKRKSKRGITIGDWKD

NEWPPERIIQYYGPATWAEDGMWGYRTPVYMLNRIIRLQAVLEIITNETAGALNLLA QQATK

MRNVIYQNRLALDYLLAQ

EEGVCGKFNLTNCCLELDDEGKVIKEITAKIQKLAHIPVQTWKG

SEQ ID NO: 139 DNA

Homo sapiens HERV-R Env >BAG58193.1 mlgmnmllitlflllplsmlkgepwegclhcthttwsgnimtktllyhtyyecagtclgt cthnqttysvcdpgrgqpyv cydpksspgiwfeihvgskegdllnqtkvfpsgkdvvslyfdvcqivsmgslfpvifssm eyysschknryahpacstds pvttcwdcttwstnqqslgpimltkiplepdyktstsnsvnltilepdqpiwttglkapl garvsgeeigpgayvylyii kktrtrstqqfrvfesfyehvnqklpeppplasnlfaqlaeniasslhvascyvcggmnm gdqwpwearelmpqdnftlt asslepapssqsiwflktsiigkfciarwgkaftdpvgeltclgqqyynetlgktlwrgk snnsesphpspfsrfpslnh swyqleapntwqapsglywicgpqayrqlpakwsgacvlgtirpsfflmplkqgealgyp iydetkrkskrgitigdwkd sewpperiiqyygpatwaedgmwgyrtpvymlnriirlqavleiitnetagalnllaqqa tkmrnviyqnrlaldyllaq eegvcgkfsltncclelddegkvikeitakiqklahipvqtwkg

Figures

[0076] The Figures show:

Figure 1 : Upregulation of MuERV (murine ERV) in donor cells increases intercellular aggregate induction. a. Intercellular protein aggregate induction by direct cell-cell contact or via EVs. Recipient N2a cells expressing soluble NM-GFP (N2a NM-GFP ^so1 ) are cocultured with donor cell clone N2a s2E, stably producing NM-HA aggregates (N2a s2E NM-HA ^a "). Alternatively, EVs isolated from conditioned medium of donor cells are added to recipient cells 1 h post-plating. Quantitative image analysis is performed with images scanned by CellVoyager6000, an automated confocal microscope, after 16 h. b. Continuous culture of donor cell clone N2a NM-HA ^a " s2E increases the aggregate induction rate in cocultured recipient N2a NM-GFP ^S0 ' cells (left panel). Increased percentage of recipient N2a NM-GFP cells with NM-GFP aggregates upon exposure to EVs derived from high passage donor cells (middle panel). Similar results were obtained when EVs from low or high passage donor clones were used to induce NM-GFP aggregation in primary cortical neurons expressing soluble NM-GFP (right panel). P7: Passage 7; P16: Passage 16. Results shown are means ± SD (n=6; ***, p<0.001; unpaired student t test). c. Western blot analysis of cell lysates and EVs from donor clone s2E cells reveals increased MuERV Env and Gag expression upon continuous cell culture. Note that Env comprises the SU subunit gp70 and the TM subunit Pr15/p15E (shown is gp70). Gag subunits include Pr65 ^Ga9 and p30. Env was detected using mAb83A25 (Env) (Evans et al. , J Virol (1990), 64: 6176-6183), Gag was detected using ab100970 (McNally et al., J Chromatogr A (2014), 1340:24-32) antibodies. d. The 100,000x g pellet from conditioned medium of donor clone s2E NM- HA ^a " (P21) was subjected to a shallow OptiPrep density gradient to separate EVs from virus particles. Twelve density gradient fractions were collected and analyzed for Alix, endogenous Env/Gag and NM-HA. Endogenous Env and Gag were detected using a goat polyclonal anti-xenotropic MuLV virus antibody ABIN457298 (antibodies-online). e. Density gradient fractions of (d) were analyzed for particle numbers using ZetaView. Fractions containing EVs or viral particles are indicated. f. Transmission electron microscopy reveals the typical cup-shaped EVs in fractions 2 and 3 and virus particles with an electron dense core in fractions 9 and 10. Scale bar: 500 nm. g. Optiprep fractions were tested for reverse transcriptase activity using a colorimetric reverse transcriptase assay.

Figure 2: Intercellular aggregate induction by EVs is greatly enhanced by MuERV

Env receptor-ligand interactions. a. Amprenavir inhibits maturation of endogenous MuERV proteins, including Env. Cell lysates and EVs derived from Amprenavir-treated donor cell clone N2a NM-HA ^a " s2E were analyzed for Env maturation by Western blot. Amprenavir-treated cell lysate and EVs lack the proteolytical mature Env transmembrane (TM) fragment p15E required for receptor binding. Cleaved products and degradation intermediates were detected by anti-MuLV virus antibody ABIN457298. Presumed bands representing Env precursor protein (gp85 and gp70), Pr15E or cleavage product (p15E) are indicated. b., c. Aggregate induction in recipient N2a NM-GFP ^so1 cells cocultured with Amprenavir-pretreated N2a NM-HA ³ " s2E donor cells or (c) in recipient cells exposed to EVs derived from Amprenavir-treated donors. d, EVs from donor clone N2a NM-HA ³ " s2E were incubated with increasing concentrations of anti-Env antibody mAb83A25 for 1 h and added to recipient N2a NMGFP ^S0 ' cells for 16 h. e, g. Donor clone N2a NM-HA ³ " s2E was transfected with three individual siRNAs (SEQ ID NO 14-19) against endogenous Env (e) or (SEQ ID NO 20- 25) against Gag (g). As control, donor cells were transfected with non silencing siRNA (-). Western blots were developed using anti-Env antibody mAb83A25 or anti-Gag antibody ab100970, respectively. f, h. Knock-down of endogenous Env (f) or Gag (h) in donor N2a NM-HA ³ " s2E cells reduces aggregate induction in recipient N2a NM-GFP ^SG| cells in coculture. Shown is the percentage of recipient cells with NM-GFP ³ " compared to the percentage of aggregate-bearing recipient cells in coculture upon donor transfection with non-silencing siRNA (set to 100%) (n=6, ***, p<0.001; one way ANOVA). i. Donor N2a NM-HA ³ " s2E cells of low passage number (P1) were treated with DNA methyltransferase inhibitors 5-azacytidine (Aza), 5-aza-2 - deoxycytidine (Dec) or DMSO for 2 d. Western blot analysis was performed 5 d post treatment using mAb83A25 (Env) and ab100970 (Gag) antibodies. GAPDH served as a loading control. j. Five days post treatment, N2a NM-HA ³ " s2E donor cells of low passage number (treatment initiated P1) were cocultured with recipient N2a NM-GFP ^SG| cells. Shown is the percentage of NM-GFP ³ " positive recipient cells cocultured with drug-treated donors compared to the percentage of NM- GFP ³ " positive recipient cells cocultured with solvent-treated donors (set to 100%) (n=6, ***, p<0.001; one-way ANOVA). k. Donor N2a NM-HA ³ " s2E cells cultured for prolonged times (treatment initiated P21) cells were treated with methyl group donors L-methionine (L-M), Betaine (B), Choline chloride (CC) or medium control for 6 days. MuERV Env and Gag protein levels were analyzed by Western blot.

L. Subsequently, cells were cocultured with recipient cells for 16 h. The percentage of NM-GFP aggregate containing recipient cells was compared to the percentage of NM-GFP aggregate bearing recipients cocultured with solvent-treated donors (set to 100%) (n=6, ***, p<0.001 ; one-way ANOVA). m. Recipient N2a NM-GFP ^so1 cells were transfected with two siRNAs against XPR1 (SEQ ID NO 26-29), siRNA against mCat-1 (SEQ ID NO 30 and 31) or with non-silencing siRNA control. mRNA knock-down was assessed 48 h post siRNA transfection by quantitative PCR. Shown is the fold change in mRNA expression in recipient N2a NM-GFP ^so1 cells normalized to cells transfected with non-silencing siRNA. n. XPR1 expression is required for EV-mediated NM-GFP aggregate induction in recipient cells. Recipient cells with downregulated XPR1 or mCat-1 expression were exposed to EVs purified from conditioned medium of donor clone s2E (P21) for 16 h. Shown is the percentage of NM-GFP ³ " bearing recipient cells transfected with XPR1 or mCat-1 siRNA compared to the percentage of NM-GFP ³ " bearing recipient cells that had been transfected with non-silencing control siRNA (set to 100%). (n=6, ***, p<0.001; one-way ANOVA). o. Recipient HEK NM-GFP ^SG| cells stably expressing HA-tagged murine XPR1. Expression of murine XPR1-HA was confirmed by Western blot analysis using anti-HA antibodies. GAPDH served as a loading control. p. Overexpression of murine XPR1-HA in recipient HEK NM-GFP ^SG| cells increases NM-GFP aggregate induction by donor-derived EVs. NM-GFP aggregate induction was measured 16 h post EV addition (n=6, ***, p<0.001; one-way ANOVA). q. Induction of Tau-GFP aggregates in N2a s2E cells. The N2a s2E NM-HA ³ " cell cone (P21) expressing high levels MuERV Env and Gag was transduced with lentivirus coding for Tau-GFP. Subsequently, cells were exposed to VSV- G pseudotyped EVs from HEK Tau-GFP ^CBD cells to induce Tau aggregates. A cell clone was isolated based on persistent Tau-GFP aggregation (Tau- GFP ^cbd ). Cell lysate (CL) and EVs (Exo) isolated from N2a s2E Tau-GFP ^CBD cells were assessed for the presence of pronase-resistant Tau. The blot was probed with Tau antibody ab64193 (Abeam). r. Tau aggregate induction in recipient HEK Tau-FusionRed ^SGl cells expressing murine XPR1-HA cocultured with Amprenavir-pretreated s2E Tau-GFP ^CBD donor cells (left panel). Tau aggregate induction in HEK Tau-FusionRed ^SGl cells expressing XPR1-HA exposed to EVs derived from Amprenavir treated donors. Note that EV-exposed recipients were also cultured in Amprenavir- containing medium to inhibit viral protein maturation in EVs (right panel). (n=6, ***, p<0.001 ; unpaired student t test). s. Donor clone s2E Tau-GFP ^CBD (left panel) or EVs (right panel) from the donor clone were incubated with increasing concentrations of anti-MuERV Env antibody for 1 h and added to recipient HEK Tau-FusionRed ^S0 ' cells expressing murine XPR1-HA for 3 d (n=6, p<0.001; unpaired student t test).

Figure 3: Viral fusogens increase EV-mediated dissemination of different proteinaceous seeds. a. Ectopic expression of VSV-G in donor cells. Donor HEK NM-HA ^a " clone C3 and N2a NM-HA ^a " clone 2E (precursor clone of s2E, poor inducer clone) were transiently transfected with a plasmid coding for VSV-G. VSV-G coated EVs were isolated 3 d post transfection and analysed by Western blot. GAPDH served as loading control. b. Expression of VSV-G by donor HEK NM-HA ^a " clone C3 or N2a NM-HA ^a " clone 2E increases EV-mediated NM-GFP aggregation in recipient HEK NM- GFP ^SG| cells. Sonication (100% for 6 min) was used to destroy EVs (n=6, ***, p<0.001 ; one-way ANOVA). c. Transient transfection of prion-infected N2a cells (N2a ^22L ) with a plasmid coding for VSV-G results in VSV-G pseudotyped EVs. EVs were harvested 3 d post transfection and analysed by Western blot. GAPDH served as a loading control. d. VSV-G pseudotyped EVs derived from prion-infected N2a ^22L cells increase infection of prion-permissive CAD5 and L929 cells. Recipient L929 and CAD5 cells were incubated with purified EVs from either mock-transfected or VSV-G plasmid transfected N2a ^22L cells. Cells were passaged 8 times before accumulation of proteinase K resistant PrP (PrP ^Sc , upper blot) and total PrP was monitored using anti-PrP mAb 4H11. e. Different tauopathy patient brain lysates show distinct pronase-resistant patterns. Brain lysates from tauopathy patients prepared in lysis buffer (PBS with 1% Triton-X and protease, phosphatase inhibitors) were subjected to 100 pg/ml pronase. Pronase-resistant Tau was detected by Western blot unsing anti-Tau antibody ab64193. Differential sensitivity to pronase suggests conformational differences of Tau aggregates depositing in different tauopathies. f. HEK Tau-GFP cell clones exposed to different tauopathy patient brain homogenates produce Tau-GFP aggregates with distinct pronase-resistant patterns. To induce Tau-GFP aggregation by patient-derived brain homogenates, a HEK cell clone stably expressing soluble Tau-GFP was exposed to brain homogenates from different tauopathy patients for 4 d. Cell populations were subsequently cloned to isolate cell lines with persistent Tau- GFP aggregates. Clones are named based on the tauopathy case from which the brain homogenate was derived. Lysates of individual cell clones were subjected to 100 pg/ml pronase treatment for 1 h at 37°C. Pronase-resistant Tau fragments were detected by Western blot using anti-Tau antibody ab64193. g. EVs isolated from HEK Tau-GFP ^a " clones contain Tau species detected with antibody against Tau (ab64193) (Sanders et al. , Neuron (2014), 82:1271- 1288). h. EVs isolated from HEK Tau-GFP ^a " clones contain pronase-resistant Tau species, as revealed by Western blot analysis using anti-Tau antibodies (ab64193). i. Presence of VSV-G in exosomal fractions of transfected Tau-GFP ^a " clones. Different HEK Tau-GFP ^a " cell clones were transiently transfected with a plasmid coding for VSV-G or were mock transfected. Presence of VSV-G was assessed by Western blot analysis. GAPDH serves as a loading control. j. 3 d later, EVs were harvested and recipient HEK Tau-FusionRed ^SGl cells were subsequently cultured with EVs or donor cells. Percentage of recipient cells with induced Tau-FusionRed aggregates following EV addition (n=6, ***, p<0.001 ; one-way ANOVA). k. Sedimentation assay of Tau in lysates of different HEK Tau-GFP ^a " donor cells and recipient HEK Tau-GFP ^SGl cells previously exposed to donor-derived VSV-G pseudotyped EVs. EV-exposed cells were cultured for 2 passages and analyzed. T: total cell lysate; S: supernatant; P: pellet. Tau-GFP was detected using anti-Tau antibody ab64193.

Figure 4: Human endogenous retrovirus proteins potentiate intercellular Tau aggregate induction. a. Workflow of Amprenavir treatment. Human T47D cells stably expressing NM-GFP or Tau-GFP were exposed to either NM fibrils or VSV-G pseudotyped EVs from corresponding cells (HEK Tau-GFP ^FTLD or Tau-GFP ^AD ) to produce cell lines with NM-GFP ^a " or Tau-GFP ^a ". Two days later, these donor cells were incubated with 10 mM Amprenavir or solvent control DMSO for 1 d. Subsequently, donor cells with NM-GFP ^a ", Tau-GFP ^FTLD or Tau- GFP ^AD aggregates were cocultured with recipient HEK NM-mCherry ^SGl or HEK Tau-FusionRed ^S01 cells, respectively, for 1 d (NM) or 3 d (Tau) in the presence of 10 mM Amprenavir or DMSO. b. Amprenavir impairs NM-mCherry aggregate induction in recipient HEK NM- mCherry ^so1 cells upon coculture with T47D NM-GFP ³ ". Percentage of recipient HEK NM-Cherry cells that harbor induced NM-mCherry aggregates. c., d. Amprenavir impairs Tau-FusionRed aggregate induction in recipient HEK Tau-FusionRed ^SGl cells upon coculture with T47D Tau-GFP ^AD or Tau- GFp ^FTLD percentage of HEK Tau-FusionRed cells that harbor Tau- FusionRed ³ " after coculture with T47D Tau-GFP ³ " donor cell lines (n=6, ***, p<0.001 ; unpaired student t test).

Figure 5: Distinct HERV Env transcripts are upregulated in postmortem brains of tauopathy patients. a-i. 9 selected HERV family members were assessed for their env transcript levels in postmortem brains of tauopathy patients. Brain samples from frontal cortex region of three AD, two CBD, two PSP and one FTLD patients, together with brain samples from pons of one CBD and one PSP patient were analyzed. HERV transcript levels in postmortem brain samples from AD, CBD, PSP and FTLD-Tau and ALS-TDP patients were compared to HERV expression levels in healthy controls. (n=3, ***, p<0.001; **, p<0.01; *, p<0.1; one way ANOVA)

Figure 6: Continuous culture of donor clone N2a NM-HA ³ " s2E upregulates

MuERV expression. a. Continuous culture of N2a NM-HA ³ " clone s2E does not increase EVs release. Numbers of microvesicles isolated from conditioned medium of cells passage 7 (P7) and 16 (P16) post thawing analyzed by ZetaView Nanoparticle Tracking (n=3; unpaired student t-test). b. Volcano plot of total cell proteome. Cell lysates of donor N2a NM-HA ³ " clone s2E at lower and higher passage number (P7 and P16) were subjected to quantitative mass spectrometry analysis. Proteins were ranked according to their p values and their relative abundance ratio (log2 fold change) for cells of P16 compared to cells of P7. c. Volcano plot of proteome of EVs derived from donor N2a NM-HA ³ " clone s2E P16 versus P7. d. Continuous culture of N2a NM-HA ³ " clone s2E increases endogenous env and gag mRNA as revealed by qRT-PCR. Shown is the fold change in expression in donor cells P16 versus P7 (n=6, ****, p<0.0001; *, p<0.1, unpaired student t test). e. To assess the release of virus particles, microvesicles were precipitated from conditioned medium of different N2a NM-HA ^a " clones using polyethylenglycol (PEG). Reverse transcriptase (RT) activities were determined using a colorimetric RT assay (Roche). Mn ²⁺ -dependent RT activity of particles released from donor clone N2a NM-HA ^a " s2E increased upon continuous passage. N2a NM-HA ^a " clones 1C and 3B released only trace amounts of RT activity even upon prolonged culture. f. Virus particles released from donor clone s2E at P17 are infectious to a murine melanocytic cell line (melan-a) susceptible to MuLV infection. Melan-a and human Hela cells were exposed for 6 d to conditioned medium of the donor clone (P17). Western blot analysis using antibody ABIN457298 against xenotropic MuLV viruses detects expression of Env and Gag only in melan-a cells. Viral proteins are indicated.

Figure 7: Protease inhibitors effective against MuLV inhibit intercellular induction of NM-GFP aggregates. a. Workflow of compound test in cocultures. Donor clone N2a NM-HA ^a " s2E and recipient N2a NM-GFP ^S0 ' cells were co-seeded and different viral inhibitors were added at three concentrations 1 h later. Twelve hours post drug treatment, donor and recipient cells were analyzed for the percentage of donor cells with NM-HA ^a " or recipient cells with induced NM-GFP ^a ". b. Effect of HIV protease inhibitors on NM aggregation in donor and recipient cells. Left panel: No effect of HIV protease inhibitors on the number of donor cells containing NM-HA ^a ". Right panel: HIV protease inhibitors, particularly Amprenavir and Atazenavir, reduce aggregate induction in recipient NM- GFP ³⁰ ' cells. c-e. Effect of reverse transcriptase inhibitors (c), HCV protease inhibitors (d) and HIV integrase inhibitors (e) on the percentage of donor and recipient cells harboring NM-HA ^a " or NM-GFP ³ ", respectively. Cells with NM aggregates (either donor or recipient) that were solvent-treated (DMSO) were set as 100%. The percentage of drug-treated cells with aggregates was normalized to the percentage of aggregate-bearing cells treated with DMSO alone.

Figure 8: Amprenavir impairs NM-GFP aggregate induction in cocultured recipient cells. a. Workflow of compound test in cocultures, in recipient cells exposed to recombinant NM fibrils or in recipient cells exposed to donor-derived EVs (P17). For cocultures, donor clone N2a NM-HA ^a " s2E (P17) and recipient N2a NM-GFP ^S0 ' cells were co-seeded and exposed to compounds 1 h later. Alternatively, recipient N2a NM-GFP ^S0 ' cells were pretreated with different concentrations of HIV inhibitors for 1 h, and cells were subsequently exposed to either recombinant fibrils (5 mM monomer equivalent) or donor-derived EVs for 12 h. Note that donor cells from which EVs were isolated remained untreated. b. Amprenavir effects on NM-GFP aggregate induction in recipient cells in the three assays (a). The inhibitory effect of Amprenavir on NM-GFP aggregate induction in recipients was observed only when donor cells were cotreated c-e. Effect of reverse transcriptase inhibitors (c), HCV protease inhibitors (d) and HIV integrase inhibitors (e) on the induction of NM-GFP aggregates in recipient cells upon exposure to NM fibrils (left graphs) or EVs from NM-HA ^a " s2E cells (P21) (right graphs). Cells exposed to fibrils were incubated with three concentrations of drugs (1, 10, 20 pM). Cells exposed to EVs were incubated with compounds (10 pM) in triplicate and data were analyzed using one-way ANOVA. Recipient cells with NM-GFP aggregates exposed to DMSO were set to 100%. Drug-treated cells were normalized to cells treated with DMSO alone.

Figure 9: Targeting MuERV protein maturation reduces NM-GFP aggregate induction in recipient cells. a. Experimental setup to test if treatment of donor cells with Amprenavir affects NM-GFP ³ " induction in recipient cells. Donor clone N2a NM-HA ³ " s2E (P21) was treated with 10 pM Amprenavir or DMSO for 3 d. Pretreated donor cells were subsequently cocultured with recipient N2a NM-GFP ^SG| cells in the absence of the drug. In a second experimental set-up, EVs isolated from Amprenavir-treated donors were added to recipient cells in the absence of Amprenavir. Aggregate induction in recipient cells was assessed 16 h later. b. Nanoparticle measurement of EVs isolated from conditioned medium of Amprenavir- and DMSO-treated donor cells. Amprenavir-treated cells released comparable amounts of particles as DMSO-treated cells. c. Donor clone N2a NM-HA ³ " s2E was incubated with anti-MuLV Env antibody mAb83A25 for 1 h. Subsequently, donor cells were cocultured with recipient N2a NM-GFP ^so1 cells for 16 h (n=6). d, e. Reduction of MuERV env (d) or gag (e) transcripts following siRNA treatment assessed by qRT-PCR. Shown are fold changes relative to non silencing control (n=3, ****, p<0.0001; one-way ANNOVA). f-h. Donor clone N2a NM-HA ³ " s2E one passage post defrosting was treated with DNA methyltransferase inhibitors 5-azacytidine (Aza), 5-aza-2 - deoxycytidine (Dec) or DMSO for 2 d and cells were subsequently incubated in the absence of the drug for 5 d. Increased expression of MuERV env (f), gag (h) and pan -env (g) transcripts in donor cells 5 d post treatment were revealed by qRT-PCR (n=3, ****, p<0.0001; one-way ANOVA) i-k. Donor cells of high passage number (P21) were treated with methyl group donors L- methionine, Betaine, Choline chloride or medium control for 6 d. MuERV env (i), gag (j) and pan -env (k) transcripts decreased after treatment with methyl group donors (n=3, ****, p<0.0001; one-way ANOVA).

Figure 10: Expression of the murine XPR1 receptor is required for efficient NM-GFP aggregate induction in recipient cells. a. Alignment of MuERV Env polyprotein P10404 overexpressed in donor cell clone N2a NM-HA ³ " s2E (P17) and the Env protein of a typical polytropic MuLV, MCF 247 (Yan et al. , Retrovirology (2009), 6:87). Shown are the variable regions VRA, VRC and VRB in the surface domain SU that determine receptor usage by different X/P-MuLV subtypes. Identical amino acid residues are indicated by dots. b, c. Murine XPR1 expression by recipient cells is required for efficient NM- GFP aggregate induction during coculture of donor and recipients, but not in fibril-induced NM-GFP aggregation. Recipient N2a NM-GFP ^SG| cells were transfected with two siRNAs against XPR1, one mCat-1 siRNA or a non silencing siRNA control (mock). Two days later, these recipient cells were subsequently cocultured with untreated donor N2a s2E cells (P21), or exposed to 5 mM NM fibrils (monomer equivalent). Aggregate induction was monitored after 16 h. The number of recipient cells with aggregates transfected with non silencing siRNA was set to 100%. Recipient cells transfected with siRNA against receptors that contained NM-GFP ³ " were normalized to non-silencing siRNA control cells with NM-GFP ³ ". d. Transmembrane structure of XPR1. The receptor contains 4 extracellular loops (ECL 1-4) (Kozak et al., Retrovirology (2010), 7:101). e. Polymorphic variants of xenotropic and polytropic (X/P-) MuLV receptor XPR1 in mouse N2a and human HEK cells. Shown are mismatches in the surface-exposed loops ECL 3 and 4. ECL3 and 4 are required for binding of X/P-MuLV (Kozak et al., Retrovirology (2010), 7:101). f. Ectopic expression of the HA epitope-tagged XPR1 receptor variant of N2a cells in HEK NM-GFP ^so1 cells drastically increases NM-GFP aggregate induction when cells are cocultured with donor clone N2a NM-HA ^a " s2E. Untransfected recipient N2a NM-GFP ^so1 served as positive controls. NM-GFP aggregate induction was measured 16 h post coculture. g. Recipient HEK NM-GFP ^SG| cells with or without XRP1-HA or untransfected N2a NM-GFP ^SG| cells were exposed to in vitro formed NM fibrils (5 mM monomer equivalent). NM-GFP aggregate induction was measured 16 h post fibril addition (n=6, ***, p<0.001; one-way AN OVA).

Figure 11 : Endogenous ERV increases Tau aggregate induction in recipient cells. a. An N2a s2E cell clone (derived from cells transduced at P21) expressing soluble Tau-GFP (s2E Tau-GFP ^SGl ) was exposed to VSV-G pseudotyped EVs isolated from conditioned medium of VSV-G transfected HEK Tau-GFP ^CBD cells to induce Tau-GFP aggregates. Limiting dilution cloning was performed to isolate single cell clones that stably propagate Tau-GFP aggregates (s2E Tau-GFP ^CBD ). b. Experimental setup of Amprenavir treatment. N2a s2E Tau-GFP ^CBD donor cells were exposed to 10 pM Amprenavir or DMSO for 1 d. Subsequently, donor cells were cocultured with recipient HEK Tau-FusionRed ^SGl XPR1-HA cells for 3 d in the presence of 10 pM Amprenavir or DMSO. c. Tau aggregate induction in recipient HEK Tau- FusionRed ^SGl XPR1-HA cells following coculture with N2a s2E Tau-GFP ^CBD was monitored via automated confocal microscopy. Coculture with control N2a s2E cells expressing soluble Tau (N2a s2E Tau-GFP ^SGl ) did not lead to Tau aggregate formation in recipient cells. Amprenavir treatment of donor cells significantly decreased Tau- FusionRed aggregate induction in recipients. Arrows indicate induced Tau- FusionRed aggregates.

Figure 12: Viral glycoproteins contribute to intercellular protein aggregate spreading. a-d. Ectopic expression of VSV-G in donor cells. Donor clones HEK NM-HA ^a " C3 and N2a NM-HA ^a " 2E (precursor of clone s2E exhibiting low intercellular aggregate induction efficiency) were transiently transfected with a plasmid coding for VSV-G. As a control, cells were transfected with empty vector. Overexpression of VSV-G in donor clone HEK NM-HA ^a " C3 increases the aggregate induction rate in cocultured N2a NM-GFP ^sol (a) or HEK NM-GFP ^so1 recipient cells (b). Overexpression of VSV-G in donor clone N2a NM-HA ^a " 2E increases the aggregate induction rate in cocultured recipient N2a NM-GFP ^so1 (c) or HEK NM-GFP ^so1 recipient cells (d) (n=6, ***, p<0.001 ; unpaired student t- test). e. Workflow of the experiment. N2a cells persistently infected with TSE strain 22L (N2a ^22L ) cells were transfected with a VSV-G coding plasmid or empty vector control. Conditioned medium was harvested and CAD5 and L929 cells were exposed to isolated EVs derived from VSV-G expressing or control N2a ^22L for 3 d. Subsequently, recipient cells were passaged 8 times to dilute out inoculum before accumulation of prions was monitored by immunofluorescence staining of guandidinium hydrochlorid- (GdnHCL-) unfolded PrP ^Sc by confocal microscopy or proteinase K resistant PrP ^Sc by Western blot. f. Accumulation of PrP ^Sc in recipient L929 and CAD5 cells was monitored via automated confocal microscopy following GdnHCI treatment and staining with anti-PrP mAb 4H11 (Ertmer et al., JBC (2004), 279:41918-41927). Arrowheads indicate PrP ^Sc signal. g. Percentage of recipient cells containing positive PrP ^Sc puncta (n=6, ***, p<0.001; unpaired student t test).

Figure 13: Overexpression of VSV-G in HEK donor cells increases Tau aggregate induction in recipient cells. a. A HEK cell clone stably expressing soluble Tau-GFP (HEK Tau-GFP ^S0 ') was exposed to 1% brain homogenates from different tauopathy patients. Limiting dilution cloning was performed to isolate single cell clones that stably propagate Tau-GFP aggregates (HEK Tau-GFP ^AD , Tau-GFP ^FTLD , Tau-GFP ^psp , Tau-GFP ^CBD ). b. Immunofluorescence staining of HEK Tau-GFP ^SGl , HEK Tau-GFP ^AD , Tau- GFp ^FTLD Tau-GFP ^psp and Tau-GFP ^CBD cells. Nuclei were stained with Hoechst. Representative, super resolution images were obtained using the LSM800 confocal microscope (Zeiss) with applied Airyscan detection. Arrows indicate Tau-GFP aggregates in different cell clones. c. Workflow of the experiment. Different HEK Tau-GFP ^a " clones were transfected with a plasmid coding for VSV-G or the empty vector as control. EVs were isolated from conditioned medium of donor cell populations. Recipient HEK cells stably expressing soluble Tau-FusionRed (HEK Tau- FusionRed ^S01 ) were either cocultured with transfected donor cells or exposed to donor-derived EVs for 3 d. d. Tau-FusionRed aggregation in recipient cells was monitored by automated confocal microscopy. Percentage of recipient cells with induced Tau- FusionRed aggregates following coculture with donors (n=6, ***, p<0.001; one way ANOVA). e, f. Tau aggregate induction in recipient HEK Tau-FusionRed ^S0 ' cells following coculture (e) or EV addition (f) was monitored by automated confocal microscopy. Arrows indicate induced Tau-FusionRed aggregates.

Figure 14: Human endogenous retroviruses contribute to the spreading of protein aggregates. a. Experimental workflow. A human breast cancer cell line MCF-7 (4) was engineered to stably express Tau-GFP and induced to propagate Tau aggregates by exposure to Alzheimer’s disease brain homogenate (AD). A single cell clone was subsequently isolated and used in the experiment (MCF- 7 Tau-GFPAD). This donor clone was treated with 2 mM 5-Aza-2-deoxycytidine (Aza) for 4 d to de-repress HERV expression. Pretreated donor cells were cocultured with HEK-Tau-FRsol cells. b. Quantitative real-time PCR demonstrating increased HERV-W Env (Syncytin-1) expression in MCF-7 cells treated with Aza. Statistics: Unpaired Student’s t-test (n=3). c. Quantitative analysis of recipient cells with induced Tau-FR aggregates following coculture with DMSO-treated or Aza-treated donor cells. Statistics: Unpaired Student’s t-test (n=6). d. Syncytin-1 was downregulated in donor MCF-7 Tau-GFPAD cells by lentiviral shRNA transduction. Recipients were subsequently cocultured with transduced donors that had been passaged at least 5 times post transduction. e. shRNA-mediated downregulation of Syncytin-1 mRNA in MCF-7 Tau- GFPAD cells assessed by quantitative real-time PCR. Statistics: Unpaired Student’s t-test (n=3). f. Quantitative analysis of recipient cells with induced Tau-FR aggregates following coculture with donors with decreased HERV-W Syncytin-1 expression. Statistics: Unpaired Student’s t-test (n=6). Figure 15: Lopinavir treatment reduces intercellular protein aggregate spreading. a. Melanoma cell line A375 (Oricchio E, Sciamanna I, Beraldi R, Tolstonog GV, Schumann GG, Spadafora C. 2007. Distinct roles for LINE-1 and HERV-K retroelements in cell proliferation, differentiation and tumor progression. Oncogene 26:4226-4233) was engineered to stably express Tau-GFP and subsequently exposed to AD brain homogenate to induce Tau aggregation. A clone stably propagating Tau-GFPagg was isolated and used for experiments. Donor A375 Tau-GFPAD cells were treated with 10 mM inhibitor Lopinavir to repress HERV-K protease for 3 d before EV were harvested. Donors or donor EV were then cultured with recipient HEK Tau-FRsol cells in the presence of 10 mM Lopinavir or DMSO for 3 d. b. Quantitative analysis of recipient cells with Tau-FRagg upon coculture with donors. Statistical analysis was performed with unpaired Student’s t-test (n=6). c. Quantitative analysis of recipient cells with induced Tau-FRagg following exposure to donor-derived EV. Statistical analysis was performed with unpaired Student’s t-test (n=3).

Figure 16: HERV-W Env interactions with its receptors increase prion and Tau aggregate induction. a. Experimental workflow. Donor HEK cells stably propagating aggregated NM-HA or Tau-GFPAD were transfected with plasmid coding for wildtype (WT) or mutated (MT) Myc epitope-tagged Syncytin-1 (Syn-Myc) and subsequently cocultured with recipient HEK cells expressing NM-GFPsol or Tau-FRsol, respectively. b. Western blot analysis of donor clones transfected with plasmid coding for wildtype (WT) or mutant (MT) Syn-Myc. c. Quantitative analysis of the percentage of recipient cells with induced aggregates upon coculture. Statistics were performed with one-way ANOVA (n=6). d. Recipient cells were transfected with empty vector or vectors coding for receptors ASCT1/2 (genes: SLC1A4/5). Cells were cocultured with donor cells expressing Syn-Myc. e. Quantitative analysis of the percentage of recipient cells with induced aggregates. Syn-Myc expressing donors were cocultured with recipient cells overexpressing the receptors (genes: SCL1A4/5) or transfected with pcDNA3.1(-) control. Statistics: Unpaired Student’s t-test (n=6). f. Expression of receptors was silenced by siRNA in recipient cells. Recipients were subsequently cocultured with donor cells expressing Syn-Myc. g. Knock-down of SCL1A4 and SCL1A5 mRNAs by specific siRNAs. Statistics: Unpaired Student’s t-test (n=3). h. Knock-down of SCL1A4/5 in recipients decreases the percentage of recipient cells with induced aggregates. Statistics: Unpaired Student’s t-test (n=6). i. Donor HEK cells propagating NM-HAagg or Tau-GFPAD were transfected with empty plasmid or plasmid coding for Syn-Myc. EV were harvested 3 d later and added to recipient HEK NM-GFPsol or Tau-FRsol overexpressing SCL1A4/5, respectively. j. Western blot demonstrating the presence of Syn-Myc in EV fraction of donor cells. Flotillin-1 and HSP70/72 served as EV markers. k. Quantitative analysis of recipient cells with induced aggregates following exposure to EV from donor cells. Statistics: Unpaired Student’s t-test (n=3).

The present invention is further illustrated by the following examples. Yet, the examples and specific embodiments described therein must not be construed as limiting the invention to such specific embodiments.

Examples

[0077] Example 1

Upregulation of endogenous retrovirus increases intercellular protein aggregate induction

The prion domain NM of the Saccharomyces cerevisiae prion protein Sup35 stably expressed in the cytosol of mouse neuroblastoma N2a cells was induced to aggregate by exposure to amyloid fibrils of recombinant NM protein (Krammer et al., PNAS (2009), 106: 462-467). To study cellular mechanisms of protein aggregate spreading, subclone N2a s2E was used, selected by two rounds of limiting dilution cloning. This clone was selected due to its ability to potently induce NM aggregation in cells expressing soluble NM upon coculture and EV addition (Liu et al., mBio (2016), 7:00915-00916). Donor clone s2E was cocultured with recipient cell line N2a expressing soluble NM-GFP (NM-GFP ^so1 ) and the percentage of recipient cells with induced NM-GFP aggregates was subsequently determined by automated microscopy (Fig. 1a). Surprisingly, it was found that aggregate induction in cocultured recipient cells was strongly increased when donor cells had been in culture over prolonged periods of time (Fig. 1b, left graph). EVs were isolated from conditioned medium of donor cell clone s2E and added to N2a NM-GFP ^so1 cells or primary cortical neurons ectopically expressing NM-GFP ^so1 (Fig. 1b, middle and right graph). Increased passage number also strongly increased EV-mediated NM aggregate induction in both N2a cells and primary cortical neurons (Fig. 1b). This effect was not due to increased EV secretion, as exosomal particle numbers did not change significantly over prolonged culture (Fig. 6a). Proteomic analyses of total cell lysates and exosomal fractions isolated from s2E donor cells passaged 7 or 16 times or passaged 6- or 15-times post cryoconservation, respectively, revealed a significant increase of endogenous retrovirus (ERV) gene products upon higher passage number ( Fig. 6b, c). The presence of ERV proteins Env and Gag was confirmed by Western blot analyses (Fig. 1c) and the presence of env and gag mRNA qRT-PCR (Fig. 6d).

It was determined whether the highly efficient aggregate induction by coculture or by EVs from donor cells of later passage was associated with active endogenous retroviral particles present in the exosomal fraction. To this end, the reverse transcriptase (RT) activity of released particles from donor cell clone s2E (P16) was compared with N2a NM-HA ^a " cell clones 1C and 3B that exhibit low aggregate induction rates in recipient cells (Hofmann et al., PNAS (2013), 10: 5951-5956; Liu et al., MBio (2016), 7). Only N2a NM-HA ^a " clone s2E released particles with increasing RT activity upon prolonged culture (Fig. 6e). Infectivity of viral particles was tested on Hela cells and murine melan-a cells, a cell line permissive for endogenous retrovirus (Li et al., Int J Cancer (1998), 76: 430-436). Interestingly, viral particles released from donors were infectious to melan-a cells. Hela cells appeared refractory to infection, suggesting that functional receptors for the endogenous virus were absent in these cells (Fig. 6f).

It was determined if endogenous retroviral particles or vesicles released by the donor cells contained infectious NM seeds. To separate EVs from viral particles, an Optiprep velocity gradient previously used to separate HIV-1 virions from non-viral extracellular vesicles was employed (Dettenhofer et al. , J Virol (1999), 73: 1460-1467). Western blot analyses revealed the presence of NM-HA predominately in fractions that contained exosomal marker Alix (Fig. 1d). Viral proteins Gag and Env were distributed throughout the gradient, with highest levels found in Alix-positive fractions (fractions 2-6) that also contained highest levels of nanoparticles (Fig. 1e). However, electron microscopy demonstrated that fractions 9 and 10 contained membranous 80-100 nm spherical particles with an electron-dense core, characteristic of g-retroviral particles (Fig. 1f), while vesicles in fractions 2 and 3 exhibited a cup-shaped morphology, characteristic of EVs (Fig. 1f). RT (Mn ²⁺ -dependent) activity was associated with viral fractions 8-11 containing only few EVs (Fig. 1e, g). Highest aggregate induction efficiency was associated with exosomal fractions, while the major viral particle fraction 10 failed to induce NM-GFP aggregation in recipient cells (Fig. 1h). This showed that increased NM aggregate seeding activity is associated with EVs isolated from conditioned medium of N2a s2E (P21) cells expressing endogenous retrovirus genes.

[0078] Example 2

ERV gene products are required for intercellular aggregate induction via EVs

Experiment 1 showed that upregulated ERV Env and Gag proteins in donor cells are associated with EVs and facilitate efficient EV-mediated aggregate transmission to recipient cells. To further investigate if EV-mediated NM aggregate induction depends on the fusogenic activity of Env, anti-HIV-1 drugs were screened for their effects on NM aggregate induction in coculture, as well on EV- and fibril-mediated NM aggregate induction in recipient cells (Figure 7a). Strikingly, treatment of cocultures with HIV-1 protease inhibitors (particularly atazanavir and amprenavir) reduced the percentage of recipient cells with NM- GFP aggregates (Figure 7b, c). By contrast, reverse transcriptase and integrase inhibitors as well as Hepatitis C virus (HCV) protease inhibitors had no effect on aggregate induction during coculture (Fig. 7d-f). Moreover, none of the compounds showed any effect on fibril- and EV-mediated aggregate induction in recipient cells (Fig. 8a-e). To test whether Amprenavir inhibited Env protein maturation in the donor cells and thus had no effect when only recipients were treated, donor cells were pre-treated with 10 mM Amprenavir for 3 days. Donors were subsequently cocultured with recipient cells in the absence of Amprenavir. Additionally, EVs isolated from Amprenavir-treated donors were tested for their aggregate induction efficiency in recipient cells (Fig. 9a). Western blot analyses of cell lysates and exosomal fractions from Amprenavir- or DMSO-treated donor cells demonstrated that Amprenavir efficiently inhibited Env protein maturation to TM p15E (Fig. 2a). Amprenavir treatment of donor cells significantly inhibited intercellular aggregate induction during coculture (Fig. 2b). Strikingly, Amprenavir treatment of donor cells also basically abolished EV-mediated aggregate induction in recipient cells (Fig. 2c), without affecting secreted particle numbers (Fig. 9b). These results demonstrate that maturation of ERV encoded gene products in donor cells or donor-derived EVs is essential for efficient aggregate induction in recipient cells.

Neutralization experiments with antibodies targeting Env protein revealed a dose-dependent reduction of NM-GFP aggregate positive recipient cells cocultured with donor cells (Fig. 9c) or exposed to EVs isolated from donor cells (Fig. 2d), confirming that Env proteins play a prominent role in intercellular aggregate transmission and induction. To silence MuERVs, s2E cells were transfected with three siRNAs targeting the specific overexpressed MuERVs Env P10404 or Gag A0A068F126 prior to coculture with recipient cells. Due to multiple integrations of ERVs, MuERV mRNA and proteins were only slightly reduced (Fig. 2e, g, Fig. 9d, e). Still, all siRNAs significantly decreased NM aggregate induction in N2a NM-GFP cells (Fig. 2f, h). These data suggest that both env- and gag-encoded components contribute to intercellular protein aggregate induction.

It was evaluated whether treatment with DNA methyl transferase inhibitors 5-Azacytidine (Aza) and Decitabine (Dec), capable of erasing epigenetic marks and thereby inducing ERV expression (Chiappinelli et al., Cell (2015), 162:974-986; Ramos et al. , Epigenetics Chromatin (2015), 8:11) would result in increased intercellular aggregate induction efficiency. Clone s2E with low MuERVs expression (P1) was chosen for the experiment. Indeed, treatment of the cell clone s2E for three days with the epigenetic drugs and subsequent culture in the absence of the drugs for 5 days resulted in increased expression of total env and gag mRNA (Fig.94f-h) and MuERV proteins (Fig. 2i). Importantly, both drugs also significantly increased NM aggregate induction in recipient cells when cocultured with pretreated donors (Fig. 2j). In a reverse experiment, we aimed to increase DNA methylation by l-methionine, betaine or choline chloride treatment of donor cells s2E (P21, high MuERV expression) to reduce MuERV expression. Pretreatment of donors decreased total env and gag mRNA (Fig. 9i-k) and MuERV proteins (Fig. 2k). Further, treatment also decreased NM- GFP aggregate induction when donors were subsequently cocultured with recipient cells (Fig. 21). We conclude that epigenetic regulation of ERV expression affects intercellular aggregate transmission.

Alignment analysis showed substantial similarity of P10404 with MCF247, a polytropic MuLV (Fig. 10a). Silencing of XPR1 but not mCat-1 (Fig. 2m) in recipient cells strongly reduced NM aggregate induction during coculture (Fig. 10b) and when recipient cells were exposed to EVs (Fig. 2n). By contrast, silencing of both receptors in recipient cells had no effect on NM aggregate induction by recombinant NM fibrils, demonstrating that NM aggregate uptake was mediated by EV-receptor contact and not direct receptor-independent internalization of released free (non-EV) NM seeds (Fig. 10c).

XPR1 is a multiple-membrane spanning receptor with eight putative transmembrane domains and four extracellular loops (ECL) (Battini et al., PNAS (1999), 96: 1385-1390). Polymorphisms in ECL 3 and 4 affect the entry of certain X/P-MuLV subtypes. Analysis of XPR1 of N2a cells demonstrated that its Env recognition domain differed at 9 residues within ECL 3 and 4 from XPR1 expressed by HEK cells (Fig. 10d, e). It was tested if direct cell contact or EVs derived from N2a donor clone s2E can also induce NM-GFP aggregation in human HEK cells. HEK cells were refractory to intercellular aggregate induction via coculture with N2a clone s2E and exposure to s2E-derived EVs, consistent with the idea that they express a non-permissive XPR1 receptor. However, expression of the N2a polymorphic XPR1 variant in HEK cells (Fig. 2o) conferred susceptibility via coculture (Fig. 10f) or EVs derived from N2a donor clone s2E (Fig. 2p). Expression of the murine polymorphic XPR1 variant had no effect on aggregate induction by recombinant NM fibrils (Fig. 10g). Thus, it was shown that efficient NM aggregate induction via coculture or EVs depends on specific Env/ receptor interactions.

To examine this effect on Tau aggregate spreading, an N2a s2E cell clone stably propagating aggregated Tau-GFP ^CBD was produced (Fig. 11a). To this end, N2a clone s2E (P21) was transdcued with lentivirus coding for Tau-GFP. Cells were subsequently exposed to VSV-G pseudotyped EVs from HEK Tau-GFP ^CBD cells (see Example 3) and individual clones were isolated that exhibited stable Tau-GFP aggregation. Cells and EVs were analyzed for the presence of aggregated Tau-GFP. Pronase-resistant Tau-GFP was found in both cell lysate and EVs (Fig. 2q). To inhibit MuERV gene product maturation, donor cells were treated with Amprenavir for three days. Donor cells and donor cell-derived EVs were subsequently exposed for three days to recipient HEK cells expressing soluble Tau- FusionRed and the murine XPR1 receptor variant required for MuERV Env interaction. Due to this long incubation time, the coculture and EV induction assays were performed in the presence of Amprenavir (Fig. 11b). Tau aggregate induction in cocultured recipient cells was low in the absence of the MuERV receptor variant XPR1, but was strongly enhanced when cells ectopically expressed murine XPR1. Importantly, inhibition of MuERV protease decreased Tau-FusionRed aggregate induction in Amprenavir-treated cocultures. Likewise, Amprenavir-treatment of EVs also decreased Tau-FusionRed aggregate induction in murine XPR1 expressing recipient cells (Fig. 2r) (Fig. 11c). Neutralization assays were performed using Env-specific antibodies to assess if Tau aggregate induction was dependent on the interaction of Env with its cognate receptor. Donor cells or EVs from donor cells were preincubated with antibodies for 1 h prior to adding them to recipient cells. As observed for the induction of NM aggregates, antibodies led to a dose-dependent reduction of the percentage of recipient cells with induced Tau aggregates in our coculture assay. Similar effects were observed when recipient cells were exposed to EVs preincubated with antibody (Fig. 2s), We conclude that upregulation of MuERV also contributes to the intercellular spreading of Tau aggregates.

[0079] Example 3

Fusogenic viral glycoproteins drastically increase intercellular transmission of proteinaceous seeds

The foregoing experiments demonstrated that upregulation of endogenous retroviruses drastically increased intercellular aggregate transmission via receptor-ligand interactions. It was tested whether the expression of unrelated viral glycoproteins that target specific membrane proteins on recipient cells might also be able to increase intercellular aggregate transmission and induction. The vesicular stomatitis virus glycoprotein VSV-G is routinely used to pseudotype viral particles for efficient uptake by a broad spectrum of target cells expressing the LDL receptor. Recently, VSV-G has been successfully used to pseudotype EVs for enhanced protein delivery to recipient cells (Meyer et al. , Int J Nanonmed (2017), 12: 3153-3170). It was tested if ectopic VSV-G expression also increased intercellular spreading of proteinaceous seeds. The N2a NM-HA ^a " clone 2E (precursor clone of s2E) and HEK NM- HA ^a " clone C3, two cell lines that are characterized by poor NM aggregate induction rates when cocultured with recipient cells, were transfected with plasmids coding for VSV-G. The presence of VSV-G on EVs isolated from both donor cell clones (Fig. 3a) strongly increased intercellular aggregate induction when EVs were added to HEK cells expressing NM-GFP ^S0 ' (Fig. 3b). Sonication of EV fractions abolished aggregate induction, arguing that intact EVs were required (Fig. 3b). Increased aggregate induction was also observed when VSV-G expressing donor cell clones were cocultured with either N2a or HEK NM-GFP ^S0 ' recipient cells (Fig. 12a-d). It was thus shown that viral fusogenic proteins of different origin expressed by donor cells can strongly increase intercellular protein aggregate transmission. It was then tested if viral glycoproteins could also promote spreading of pathogenic protein aggregates between cells. Thus, the effect of VSV-G expression on the intercellular spreading of transmissible spongiform encephalopathy (TSE) agents was evaluated. TSE agents, the so far only bona fide mammalian prions, are composed of misfolded cellular prion protein PrP. The conversion of cellular (PrP ^c ), a protein tethered to the cell membrane by a glycosylphosphatidyl-anchor, into its infectious aggregated isoform (PrP ^Sc ), occurs on the cell surface or along the endocytic pathway. It has previously been shown that N2a cells release prion infectivity associated with EVs. N2a cells persistently infected with TSE strain 22L (N2a ^22L ) were transiently transfected with control plasmid or a plasmid coding for VSV-G. EVs were isolated from medium of transfected cells containing VSV-G (Fig. 3c). Murine fibroblast cell line L929 (Wolf et al., J Virol (2015), 89: 9853-9864) and CAD5 cells (Mahal et al. , PNAS (2007), 104: 20908-20913), two cell lines highly permissive to TSE strain 22L, were then exposed to EVs from VSV-G transfected N2a ^22L donor cells for three days. Treated recipient L929 and CAD5 cells were subsequently cultured in the absence of EVs for more than 8 passages and tested for the formation of PrP ^Sc by Western blot and confocal microscopy (Fig. 12e). VSV-G expression drastically increased the number of cells containing PrP ^Sc aggregates, as revealed by confocal microscopy (Fig. 12f, g) and also strongly increased total PrP ^Sc , as determined by proteinase K treatment of cell lysates followed by Western blot analysis (Fig. 3d).

We further tested if VSV-G expression also increased the intercellular transmission of Tau aggregates and subsequent induction of Tau aggregation in a reporter cell line. To this end, we established a Tau cell model that had been described previously by Diamond and coworkers (Sanders et al., Neuron (2014), 82:1271-1288). HEK cells were engineered to stably express the aggregation competent Tau core spanning amino acid residues 244-372 with two point mutations P301 L/V337M fused to GFP (hereafter termed Tau-GFP). Cells were exposed to brain homogenates from patients who had suffered from Alzheimer’s disease (AD), cortical basal degeneration (CBD), progressive supranuclear palsy (PSP) or frontotemporal lobar degeneration (FTLD). Upon limiting dilution cloning, cell clones HEK Tau-GFP ^AD , Tau-GFP ^FTLD Tau-GFP ^psp and Tau-GFP ^CBD stably producing Tau aggregates were established (Fig. 13a, b). Cell lysates and exosomal fractions of individual Tau cell lines were subjected to pronase treatment to reveal differential sensitivities to proteolysis. All different tauopathy patient seeds induced Tau-GFP aggregation, revealed by the resistance to pronase treatment. Interestingly, clones were associated with different pronase-resistant patterns, in line with different pronase-resistant Tau aggregate patterns induced by different tauopathy seeds (Fig. 3e, f). Protease-resistant Tau-GFP was also found in EV fractions isolated from conditioned medium of HEK Tau-GFP ^AD , Tau-GFP ^FTLD Tau-GFP ^psp and Tau- GFP ^CBD clones (Fig. 3g, h). To pseudotype EVs, VSV-G was transiently expressed in individual clones, and cells were subsequently cocultured with recipient HEK cells expressing the soluble Tau aggregation domain fused to FusionRed (hereafter termed Tau-FusionRed) for three days (Fig. 13c). Alternatively, recipient cells were exposed to EVs isolated from VSV-G expressing donor clones for three days. Expression of VSV-G by donor cells drastically increased induction of Tau-FusionRed aggregates in recipient cells via coculture (Fig. 13d, e). Likewise, VSV-G pseudotyped EVs (Fig. 3i) also drastically increased Tau aggregate induction in recipients (Fig. 3j, Fig. 13f). Furthermore, VSV-G pseudotyped EVs isolated from four donor clones induced detectable Tau-GFP aggregates (Fig. 3k) in recipient HEK cells expressing soluble Tau-GFP cells. It was thus shown that viral fusogenic proteins can pseudotype EVs and mediate efficient intercellular aggregate transmission and induction of pathogenic proteins.

[0080] Example 4

Human endogenous retrovirus proteins contribute to intercellular protein aggregate transmission

To examine the effect of endogenous HERVs on protein aggregate transmission, T47D human breast tumor cells which exhibit highly increased HERV-K expression upon stimulation with female steroid hormones were used (Ono et al. , J Virol (1987), 61: 2059- 2062). It was first tested if HERV-K proteins contribute to the intercellular transmission of the model prion NM described above. To this end, a T47D cell clone stably expressing soluble NM-GFP (T47D NM-GFP ^so1 ) was exposed to in vitro formed NM fibrils for one day. The resulting T47D NM-GFP ³ " bulk cell population was cocultured with recipient HEK NM- mCherry ^so1 cells in the presence or absence of Amprenavir, shown to also be effective against HERV-K (Tyagi et al., Retrovirology (2017), 14:21) (Fig. 4a). While the receptor for HERV-K is unknown, HEK cells efficiently bind and internalize HERV-K Env pseudotyped HIV viruses (Lee et al., PLoS Pathog (2007), 3: e10; Kramer et al., Virology (2016), 487: 121- 128). Importantly, Amprenavir treatment of cocultures reduced the number of recipient cells with induced NM-mCherry aggregates compared to the DMSO control, suggesting that HERV protein processing was required for efficient intercellular aggregate transmission and subsequent induction of new aggregates in recipient cells (Fig. 4b).

To examine the effect of HERV-K proteins on Tau aggregate spreading, a T47D donor cell line stably expressing Tau-GFP ^SGl was generated. As exposure of T47D cells to brain homogenates resulted in poor Tau-GFP aggregation (less than 0.5 % of recipient cells), VSV-G pseudotyped EVs derived from HEK Tau-GFP ^AD and Tau-GFP ^FTLD cells (see Fig. 3k) were used to induce aggregation of Tau-GFP in T47D cells. T47D bulk populations with Tau- GFP ^AD or Tau-GFP ^FTLD were pretreated for one day with 10 mM Amprenavir or DMSO, and cells were subsequently cocultured with recipient HEK Tau-FusionRed ^S0 ' cells in the presence or absence of Amprenavir. A significant decrease in Tau aggregate induction in recipient cells was observed when cells were treated with the viral protease inhibitor (Fig. 4c, d). These results showed that expression of mature endogenous HERV proteins contributes to intercellular protein aggregate transmission. Importantly, it was shown that intercellular spreading of both non-pathogenic and pathogenic protein aggregates in HERV expressing cells can be reduced by drugs that prevent HERV protein maturation.

Elevated transcripts of distinct HERV families in postmortem brains from different tauopathy patients

The foregoing experiments indicated that murine and human ERV proteins expressed by donor cells facilitate efficient cell-to-cell and EV-mediated spreading of proteopathic seeds from donor to recipient cells. To test if HERV env expression is upregulated in tauopathies, quantitative real-time PCR was performed using predesigned primer sets against env sequences of nine HERV family members (de Parseval et al. , J Virol (2003), 77:10414- 10422; Strissel et al., Oncotarget (2012), 3:1204-1219). These primer sets locate in the coding elements that detect the expression of the coding copies of the env genes. It was found that transcripts of distinct HERVs were elevated in postmortem brain samples from individuals suffering from different tauopathies (Fig. 5). HERV-W env expression was highly upregulated in all three postmortem AD brains. By contrast, HERV-FRD, HERV-H and HERV-R(b) env transcripts were increased in all CBD brains tested. HERV-K and HERV- F(c)1 env expression was upregulated in three PSP patient samples.

Methods

Human brain samples

Frozen brain tissue samples from neuropathologically confirmed cases of AD, CBD, PSP and controls were provided by Brain Bank Tubingen.

Ethics statement

For all the patient sample experiments, the ethical approval has been obtained from ^' Medizinische Fakultat Ethik-Kommission, Rheinische Friedrich-Wilhelms-Universitat, Project no. 236/18(2018) ^' .

Molecular cloning For the expression of lentiviral constructs Tau-GFP and Tau-FusionRed, the four repeat domain 4RN1 of human Tau (amino acid residues 244 to 372) containing the mutations P301L and V337M was fused aminoterminally to GFP or FusionRed (Evrogen) with an 18- amino acid flexible linker (EFCSRRYRGPGIHRSPTA), as described previously (Woerman et al. , PNAS (2016), 113:E8187-E8196). Coding regions were cloned into the lentiviral vector pRRL.sin.PPT.hCMV.Wpre via BamHI and Sail (Hofmann et al., PNAS (2013), 10: 5951- 5956). Murine and human receptor XPR1 were amplified from cDNA of N2a or HEK cells, respectively. The coding region of murine XPR1 tagged aminoterminally with a hemagglutinin epitope (HA) was cloned into a PiggyBac expression vector PB510B-1 (System Biosciences) using Xbal and Notl restriction sites.

Cell lines

N2a, Hela, L929, CAD5 and HEK293T cells are from ATCC and were cultured in Opti-MEM (Gibco) supplemented with glutamine, 10 % (v/v) fetal bovine serum (FCS) (PAN-Biotech GmbH) and antibiotics. Melan-a cells are from Wellcome Trust Functional Genomics Cell Bank and were cultured in RPMI 1640 (Gibco) with 2 mM glutamine, 10 % FCS, antibiotics and 200 nM 12-0-tetradecanoyl phorbol acetate PMA and incubated at 37 °C and 10 % C0 ₂ . T47D cells were cultured in DMEM (Gibco) supplemented with 2 mM Glutamine and 10 % (v/v) FCS. Cells were incubated at 37 °C and 5 % C0 ₂ . The total numbers of viable cells and the viability of cells were determined using the Vi-VELL™XR Cell Viability Analyzer (Beckman Coulter).

Isolation of cortical neurons

Preparation of cortical neurons was performed using postnatal day 13 SWISS pups as described previously (Hofmann et al., PNAS (2013), 10: 5951-5956). Neurons were transduced with lentivirus 2 days post preparation on 96 well plates or Sarstedt 8 slice chambers. After 2 days, EVs were added and neurons were incubated for 2 days. Subsequently, neurons were fixed for microscopy and imaging analysis.

Production and transduction with lentiviral particles

HEK293T cells were cotransfected with plasmids pRSV-Rev, pMD2.VSV-G, pMDI.g/pRRE (all plasmids were published in Dull T, Zufferey R, Kelly M, Mandel RJ, Nguyen M, Trono D, Naldini L A third-generation lentivirus vector with a conditional packaging system. J Virol. 1998 Nov . 72(11):8463-71), and pRRI.sin.PPT.hCMV.Wpre (plasmid published in Follenzi, A. and L. Naldini (2002) HIV-based vectors. Preparation and use. Methods in molecular medicine 69: 259-274) containing Tau-GFP/FusionRed. Supernatants were harvested 30 and 54 h later and concentrated using PEG according to published protocols (Follenzi et al., Methods Mol Med (2002), 69:259-274). Cell lines and primary neurons were transduced with lentivirus, and stable cell clones expressing Tau-GFP/-FusionRed were produced by limiting dilution cloning (Krammer et al. , PNAS (2009), 106:462-467).

EV isolation

To prepare EV-depleted medium, FCS was ultracentrifuged at 100,000 x g for 20 h at 4 °C. Medium supplemented with the EV-depleted FCS and antibiotics was subsequently filtered through 0.22 mM and a 0.1 pM filter-sterilization devices (Millipore). For EV isolation, 2-4 x10 ⁶ cells were seeded in T175 flasks in 35 ml EV-depleted medium to reach confluence after 3 days. Cells and cell debris were pelleted by differential centrifugation (300 x g, 10 min; 2,000 x g, 20 min; 16,000 x g, 30 min, 4 °C). The remaining supernatant (conditioned medium) was subjected to ultracentrifugation at 100,000 x g for 1 h at 4 °C using rotors Ti45 or SW32Ti (Beckman Coulter). The pellet was rinsed in PBS and spun again using rotor SW55Ti at 100,000 x g for 1 h at 4 °C.

Aggregate induction assay

Recipient cells were cultured on CellCarrier-96 plates or 384 black microplates (PerkinElmer) at appropriate cell numbers for 1 h, and then treated with 5-10 pi of prepared samples (isolated EVs or recombinant NM fibrils). For aggregate induction by coculture, recipient and donor cells were mixed at different ratios based on the population doubling time of donor and recipient cells, and a total of 10 ⁴ cells / per well was plated. After additional incubation for 16 h or 72 h (NM or Tau, respecitively), cells were fixed in 4 % paraformaldehyde and nuclei were counterstained with 4 pM Hoechst for 15 min. Cells were imaged with the automated confocal microscope CellVoyager CV6000 (Yokogawa Inc.) using a 20 x or 40 x objective. Maximum intensity projections were generated from Z-stacks. Images from 16 fields per well were taken. On average, a total of 3-4x10 ⁴ cells per well and at least 3 wells per treatment were analyzed.

Sample preparation for mass spectrometry

Cell pellets from five s2E cell culture replicates, and six replicates of EV pellets harvested from conditioned medium of s2E cells at passages 7 and 16 were collected for a quantitative proteomics analysis. Cell pellets were lysed in 150 pL SDT buffer (4 % SDS (w/v), 100 mM Tris/HCI pH 7.6, 0.1 M DTT) by homogenization with a dounce tissue grinder and heated for 3 min at 95 °C. Samples were sonicated 5 times for 30 s with intermediate cooling using a vialtweeter sonifier (amplitude 100 %, duty cycle 50 %; Hielscher, Germany). EV pellets were lysed in 100 pL STET lysis buffer (150 mM NaCI, 50 mM TrisHCI pH 7.5, 2 mM EDTA, 1 % Triton X-100) on ice for 30 min with intermediate vortexing. Cell debris was removed by centrifugation at 16,000 ^c g for 5 min. The protein concentration was determined using the colorimetric 660 nm assay (Thermo Fisher Scientific). For cell lysates, the assay solution was supplemented with the ionic detergent compatibility reagent (Thermo Fisher Scientific). A protein amount of 30 pg per sample for cell lysates and 10 pg for EV lysates was subjected to proteolytic digestion using the filter aided sample preparation (FASP) protocol (Wisniewski et al. , Nat Methods (2009), 6:359-362) with 30 kDa Vivacon spin filters (Sartorius, Germany). Proteolytic peptides were desalted by stop and go extraction (STAGE) with C18 tips (Rappsilber et al., Anal Chem (2003), 75:663-670). The purified peptides were dried by vacuum centrifugation. Peptides from cell lysates and EV samples were dissolved in 40 or 20 pL of 0.1 % formic acid, respectively.

LC-MS/MS analyses

Samples were analyzed by LC-MS/MS for relative label free protein quantification. A peptide amount of approximately 1 pg per sample was separated on a nanoLC system (EASY-nLC 1000, Proxeon - part of Thermo Fisher Scientific) using in-house packed C18 columns (50 cm or 30 cm x 75 pm ID, ReproSil-Pur 120 C18-AQ, 1.9 pm, Dr. Maisch GmbH, Germany) with a binary gradient of water (A) and acetonitrile (B) containing 0.1 % formic acid at 50°C column temperature and a flow rate of 250 nl/min. Peptides from cell lysates were separated on a 50 cm column using a gradient of 250 min length, whereas a 183 min gradient on a 30 cm column was used for peptides from EV samples (250 min. gradient: 0 min., 2 % B; 5 min., 5 % B; 185 min., 25 % B; 230 min., 35 % B; 250 min., 60 % B; 183 min. gradient: 0 min., 2 % B; 3:30 min., 5 % B; 137:30 min., 25 % B; 168:30 min., 35 % B; 182:30 min., 60 % B). The nanoLC was coupled online via a nanospray flex ion source (Proxeon - part of Thermo Fisher Scientific) equipped with a PRSO-V2 column oven (Sonation, Germany) to a Q- Exactive mass spectrometer (Thermo Fisher Scientific). Full MS spectra were acquired at a resolution of 70,000. The top 10 peptide ions were chosen for Higher-energy C-trap Dissociation (HCD) with a normalized collision energy of 25 %. Fragment ion spectra were acquired at a resolution of 17,500. A dynamic exclusion of 120 s was used for peptide fragmentation.

Data analysis and label free quantification

The raw data was analyzed by the software Maxquant (maxquant.org, Max-Planck Institute Munich) version and 1.5.5.1 (Cox et al., Mol Cell Proteomics (2014), 13:2513-2526). The MS data was searched against a fasta database of Mus musculus from UniProt including also non-reviewed entries supplemented with databases of lentiviruses and murine leukemia viruses (download: December 09 ^th 2017, 52041 + 712 + 43 entries). Trypsin was defined as protease. Two missed cleavages were allowed for the database search. The option first search was used to recalibrate the peptide masses within a window of 20 ppm. For the main search, peptide and peptide fragment mass tolerances were set to 4.5 and 20 ppm, respectively. Carbamidomethylation of cysteine was defined as static modification. Acetylation of the protein N-term as well as oxidation of methionine were set as variable modifications. The false discovery rate for both peptides and proteins was adjusted to less than 1 %. Label free quantification (LFQ) of proteins required at least two ratio counts of razor peptides. Only unique and razor peptides were used for quantification.

The LFQ values were log ₂ transformed and a two sided Student’s t-test was used to evaluate statistically significant changed abundance of proteins between cell lysates from passages 16 and 7 as well as EV lysates from passages 15 and 6. A p-value less than 5 % was set as significance threshold. Additionally, a permutation based false discovery rate estimation was used to account for multiple hypotheses (Tusher et al., PNAS (2001), 98:5116-5121).

OptiPrep density gradient

For separating EVs and virus, the discontinuous iodixanol gradient in 1.2 % increments ranging from 6 to 18 % were prepared as previously described (Dettenhofer et al., J Virol (1999), 73:1460-1467). The 100,000x g pellet from 1050 ml culture supernatant (30 T175 flasks) was resuspended in 1ml PBS and overlaid onto the gradient. The gradient was subjected to high-speed centrifugation at 100,000 x g for 2 h at 4 °C using a SW41Ti rotor (Beckman Coulter). 12 fractions of 1ml each were collected from the top of the gradient, diluted with PBS in 5 ml, and centrifuged at 100,000 x g for 1 h at 4 °C. The pelleted fractions were resuspended in 100 pi PBS, and then used for further experiments. The reverse transcriptase activity of the viruses was measured by using a colorimetric reverse transcriptase assay (Roche).

Determination of extracellular vesicles size and number

ZetaView PMX 110-SZ-488 Nano Particle Tracking Analyzer (Particle Metrix GmbH) was used to determine the size and number of isolated extracellular vesicles. The instrument captures the movement of extracellular particles by utilizing a laser scattering microscope combined with a video camera. For each measurement, the video data is calculated by the instrument, resulting in a velocity and size distribution of the particles. For nanoparticle tracking analysis, the Brownian motion of the vesicles from each sample was followed at 22 °C with properly adjusted equal shutter and gain. At least six individual measurements of 11 subvolumes (positions) within the measurement cell and around 2200 traced particles in each measurement were detected for each sample. Electron microscopy (EM)

EM imaging of extracellular vesicle preparations was performed as previously described (Thery et al. , Curr Protoc Cell Biol (2006), Chapter3:Unit322). Briefly, the 100,000 x g pellets from conditioned medium were fixed in 2 % paraformaldehyde, loaded on glow discharged Formvar / carbon-coated EM grids (Plano GmbH), contrasted in uranyl-oxalat (pH 7) for 5 min and embedded in uranyl-methylcellulose for 5 min. Samples were examined using a JEOL JEM-2200FS transmission electron microscope at 200 kV (JEOL).

Infectivity assay

The infectivity assay was performed as previously described (Pothlichet et al., Int J Cancer (2006), 119:815-822). Briefly, melan-a cells were exposed to conditioned medium from different cell clones at either low or high passsages in the presence of 4 pg polybrene/ml for 24 h. The medium was then replaced with normal culture medium. After five days, cells were lysed for western blot analysis of retroviral Env and Gag proteins.

Drug treatments

The treatment of cells with Amprenavir (10mM; Santa Cruz) and DMSO was performed for 72 h in EV-depleted medium in T175 flasks. Afterwards, the total numbers of viable cells and the viability upon drug treatment were determined using the Vi-VELL™XR Cell Viability Analyzer (Beckman Coulter). EVs were isolated from the conditioned medium via ultracentrifugation and processed for the aggregate induction assay as described above. NM aggregate induction by coculture of donor and recipient cells or by exposure of recipient cells to donor- derived EVs was performed in the absence of the drugs. For coculture and EV treatment of recipient Tau-FusonRed cells, donor s2E P21 or T47D cells with Tau-GFP aggregates were pretreated as above. Isolated EVs or pretreated donor cells were then inucbated with recipient cells in the presence of compounds for 72 h.

To inhibit methyltransferases, s2E P1 donor cells were treated for three days with methyltransferase inhibitors 5-Azacytidine (Aza) 200 nM, Decitabine (Dec) 100 nM or DMSO as solvent control. Subsequently, the cells were cultured in the absence of the drugs for 5 days. Pre-treated donor cells were subsequently cocultured with recipient cells as described above to monitor aggregate induction efficiency in recipient N2a NM-GFP ^so1 cells. Cell lysates of donor cells were also analyzed for MuERV Env and Gag expression levels by western blot. To increase DNA methylation, the s2E donor clone (P21) was treated with methyl group donors L-methionine (L-M) 80 mM, Betaine (B) 80 mM, Choline chloride (CC) 20 mM or medium control for 6 days. MuERV Env and Gag protein levels were analyzed by western blot. Subsequently, cells were cocultured with recipient cells for 16 h. The percentage of aggregate containing recipient cells was compared to the percentage of aggregate bearing recipients cocultured with solvent-treated donors.

Neutralization assay

To block MuLVs Env on the surface of the donor cell clones s2E and s2E Tau-GFP ^CBD and on secreted EVs,, mAb83A25, reactive against a broad range MuLVs (Evans et al., J Virol (1990), 64:6176-6183) was incubated with either EVs or donor cells in serial dilutions for 1 h at 37 °C with rotation at 20 rpm. Donor cells were subsequently mixed with recipient cells for 16 h. Alternatively, antibody-treated and untreated EVs were added to recipient cells for 16 h (NM) or 3 days (Tau) incubation time.

Transfection of siRNAs and plasmids

To transiently knock-down the upregulated specific MuLV Env and Gag genes in s2E clones, custom-designed Silencer select siRNAs (Thermo Fisher Scientific) against AA037244.2 (env) and AID54952 (gag) were used. Pre-designed siRNAs against murine XPR1 and mCat-1 genes were used to knock-down genes coding for putative receptors. For transfection, 2-4 x 10 ⁵ cells/well were seeded on 6 well plates. The next day, 30 nM siRNA or plasmid DNA was transfected using Lipofectamine RNAiMAX or Lipofectamine2000 transfection reagent, respectively, according to the manufacturer’s instructions (Thermo Fisher Scientific). After 2 days, transfected cells were harvested for aggregate induction assays and qRT-PCR, western blot analysis.

PK treatment for detection of PrP ^Sc

Cells from one well of 6 well plate were lysed in 1ml lysis buffer. 900 pi of lysates were digested with 20 pg/ml proteinase K (PK) at 37 °C for 30 min for PrP ^Sc detection. Proteolysis was terminated by adding 0.5 mM Pefabloc. To make the pellet visible, 10 mI blue dextran was added to each sample and the samples were centrifuged at 20,817 x g for 1 h. Proteins in 100 mI untreated lysates were precipitated with 4 x methanol overnight at -20 °C and pelleted at 2,120 x g for 25 min at 4 °C. Untreated samples were analysed with the PK- treated pellets for total PrP and PrPSc by western blot using monoclonal anti-PrP antibody 4H11.

Sedimentation Tau polymers

The sedimentation assay was performed as described previously (Sanders et al., Neuron (2014), 82:1271-1288). Briefly, cell pellets were lysed in lysis buffer (150 mM NaCI (w/v), 50 mM (v/v) Tris-HCI, pH7.5, 1 % (v/v) NP-40, protease inhibitor) on ice for 30 min. Cleared cell lysates were separated from cell debris by centrifugation at 2650 x g for 2 min at 4 °C. Cleared cell lysates adjusted to 100 pg total protein were subjected to centrifugation at 100,000 x g for 1 h, 4 °C. Pellets were washed with 1.5 ml PBS and insoluble material was pelleted again at 100,000 x g for 30 min. Proteins in the supernatant fractions were precipitated with 4 x methanol overnight at -20 °C and pelleted at 2,120 x g for 25 min at 4 °C (soluble fraction). The pellet (insoluble fraction) and 1/3 of the soluble fraction dissolved in RIPA buffer with 4 % SDS were loaded for western blot analysis.

Pronase digestion of Tau

The resistance of Tau aggregates to pronase treatment was probed as described previously (Sanders et al., Neuron (2014), 82:1271-1288). Briefly, 18 mI cleared cell lysates or brain homogenates (containing a total protein concentration of 20-100 pg dependening on Tau aggregates content) were incubated with 2 mI 1 mg/ml pronase (Roche) at 37 °C for 1 h. Afterwards, samples were boiled in 4 x sample buffer with 1 % SDS final. Pronase-resistant Tau bands were detected by western blot as described below with rabbit anti-Tau ab64193 (Abeam).

Preparation of brain homogenates

Frozen human brain samples were homogenized in complete OptiMEM culture medium (for cell culture), QIAzol lysis reagent (for RNA isolation) or lysis buffer (PBS with 1 % Triton-X and protease, phosphotase inhibitors for protein analysis) using the Precellys® 24 (Bertin Instruments) with 1.4 mm ceramic beads at 4 °C for 4 cycles 5500 rpm 20 sec. For 10 % brain homogenates for aggregate induction in cell cultures, crude homogenates were cleared of cell debris at 872 x g for 5 min at 4 °C. Supernatants were sonicated at 50 % power for 6 min and stored at -80 °C. RNA was isolated using the Qiagen RNeasy Lipid Tissue Mini Kit combined with genomic DNA digestion as described in the manufacturer ^' s instruction. For protein analysis, brain homogenates were cleared of cell debris at 15000 x g for 15 min, 4 °C.

Tau aggregate induction using patient-derived brain homogenate

To test the Tau aggregate induction by brain homogenates from different tauopathy patients, HEK Tau-GFP ^so1 cells were plated on a CellCarrier-96 black microplate (PerkinElmer) at 2000 cells/well in 50mI complete medium. The next day, 6 pi 10 % brain homogenate and 0.2 pi Iipofectamine2000 were diluted into OptiMEM without antibiotics (final 60 mI) for 20 min at RT. Brain homogenate-liposome mixtures were added to recipient cells for 5 h and 50 mI complete medium were added to cells afterwards. The induced cells were fixed 3 days later in 4 % paraformaldehyde. Nuclei were counterstained with Hoechst. Cells were imaged using the automated confocal microscope CellVoyager CV6000 (Yokogawa Inc.) and a 40x objective. qRT-PCR

Total RNA from cell pellets or brain samples was isolated using the RNeasy Mini Kit or RNeasy Lipid Tissue Mini Kit (Qiagen). RNA concentration and quality were determined using the Agilent 2100 Bioanalyzer System. For a 20 pi reaction, 1 pg RNAs were reversely transcribed to cDNA using the iScript™ cDNA Synthesis Kit (Bio-Rad). For a 20 pi qRT-PCR reaction, 2 mI of synthesized cDNA was used as template. For qRT-PCR of murine env AA037244.2 and gag AID54952, custom designed TaqMan probes were used (Thermo Fisher Scientific). Pre-designed TaqMan probes by the company for murine pan-env, xpr1, mcat-1 and gapdh as housekeeping control and TaqMan™ Gene Expression Master Mix (Thermo Fisher Scientific) were used. qRT-PCR using TaqMan probes was performed as described in the manufacturer ^' s instruction. For qRT-PCR analyses of HERV family members, primers were designed using the corresponding cDNA sequences (cf. SEQ ID NOs. 73-92). PowerUP SYBR™ Green Master Mix (Thermo Fisher Scientific) was mixed with different cDNAs and corresponding primers as indicated in the instruction. The fast cycling mode was used for all primers.

Western Blotting

For Western blot analysis, protein concentrations were measured using the Quick Start™ Bradford Protein assay (Bio-Rad). Proteins were separated on NuPAGE®Novex® 4-12 % Bis-Tris Protein Gels (Life Technologies) followed by transfer onto a PVDF membrane (GE Healthcare). Western blot analysis was performed using rat hybridoma anti-MuERV Env mAb83A25; anti-xenotropic MuLV virus antibody ABIN457298 for detecting both Env and Gag (antibodies-online); mouse anti-MuERV Gag ab100970 (Abeam); mouse anti-Alix (1:1000; BD Bioscience); rat anti-HA 3F10 (1:1000; Roche); mouse anti-GAPDH 6C5 (1:5000; Abeam); mouse anti-Hsc/Hsp70 N27F3-4 (1:1000; ENZO); mouse anti-VSV-G A5977 (Sigma); rabbit anti-Tau ab64193 (Abeam); mouse anti-HERV K Env HERM-1811-5 (Amsbio); mouse anti-HERV K Gag HERM-1841-5 (Amsbio). The membrane was incubated with Pierce™ ECL Western Blotting Substrate (Thermo Fisher Scientific) according to the manufacturer ^' s recommendations.

Image Analysis

The image analysis was performed using the CellVoyager Analysis support software. An image analysis routine was developed for single cell segmentation and aggregate identification (Yokogawa Inc.). The total number of cells was determined based on the Hoechst signal, and recipient cells were detected by their GFP/FusionRed signal. Green aggregates were identified via morphology and intensity characteristics. The percentage of recipient cells with aggregated NM-GFP or Tau-FusionRed / Tau-GFP was calculated as the number of aggregate-positive cells to total recipient cells set to 100 %. False positive recipient cells were detected due to the heterogeneity of Tau-GFP/-FusionRed expression of individual cells. The mean percentage of false positives determined in control recipient cells was subtracted from all samples. Of note, negative values were sometimes obtained when no induction was observed. For data presentation, the minimum of the Y Axis was set to 0.

Immunofluorescence staining and confocal microscopy analysis of prion-infected cells

Cells were fixed in 4 % paraformaldehyde for 20 min at 37 °C and permeabilized in 0.1 % Triton X-100 for 10 min at RT. For PrP ^Sc staining, proteins were denatured in 6 M guanidine hydrochloride for 10 min at RT to reduce PrP ^c staining and increase detection of PrP ^Sc (Taraboulos et al., J Cell Biol (1990), 110:2117-2132). Cells were rinsed with PBS, blocked in 0.2 % gelatine for 1 h and incubated for 2 h with anti-PrP 4H11 antibody hybridoma solution diluted 1:10 in blocking solution (Ertmer et al., JBC (2004), 279:41918-41927). After three washing steps in PBS, cells were incubated for 1 h with Alexa Fluor 488- conjugated anti- Mouse IgG secondary antibody diluted 1:800 in blocking solution (Thermo Fisher Scientific) and nuclei were counterstained for 15 min with 4 pg/ml Hoechst 33342 (Molecular Probes). 96 well plate was scanned with CellVoyager CV6000 (Yokogawa Inc.). Confocal laser scanning microscopy was performed on a Zeiss LSM 800 laser-scanning microscope with Airyscan (Carl Zeiss).

Statistical analysis

All analyses were performed using the Prism 6.0 (GraphPad Software v.7.0c). Statistical inter-group comparisons were performed using the one-way ANOVA with a Bonferroni post test or Student’s t test p values smaller than 0.05 were considered significant. All experiments were performed in triplicates or sextuplicates and repeated at least three times. Error bars represent the standard deviation (SD).

[0081] Example 5

Downregulation of HERV-W Env Syncytin-1 reduces intercellular aggregate spreading

Human endogenous retroviruses (HERV) are usually silenced but become de-repressed during aging and in several human malignancies, including cancer, inflammatory diseases and neurodegeneration. To assess if HERV expression could affect intercellular spreading of protein aggregation, the inventors first made use of two cancer cell lines known to overexpress HERV. Human breast cell line MCF-7 was engineered to stably express Tau- GFP and exposed to AD brain homogenate to isolate clones propagating Tau-GFPAD. Cells were incubated with or without 5-Aza-2-deoxycytidine (Aza) for HERV de-repression and subsequently cocultured with recipient HEK Tau-FRsol cells (Fig. 14a). Aza treatment enhanced Syncytin-1 mRNA levels (Fig. 14b) and also increased recipient cells with aggregates in cocultures (Fig. 14c). Further, shRNA-mediated downregulation of Syncytin-1 expression in donor cells (Fig. 14d, e) significantly decreased induction of Tau-FR aggregates in cocultured recipients, suggesting that Syncytin-1 was involved in Tau aggregate spreading (Fig. 14f).

HIV protease inhibitor known to inhibit HERV-K maturation reduces intercellular aggregate spreading

The inventors further genetically engineered human A375 melanoma cells to express Tau- GFP and exposed them to AD brain homogenate to isolate a clone propagating Tau-GFPAD. Cells were treated with 10 mM Lopinavir, an HIV protease inhibitor shown to inhibit HERV-K protease required for HERV protein maturation. Upon coculture, the inventors observed a significant reduction of recipient cells with aggregates (Fig. 15a, b). Similarly, EV derived from Lopinavir-treated donors exhibited reduced Tau aggregate inducing activity in recipients (Fig. 15c). Combined, these data suggest that HERV could contribute to intercellular aggregate induction. The fact that HIV protease inhibitor Lopinavir also affected protein aggregate induction further suggests that HERV protease inhibitors represent promising drugs to inhibit proteopathic seed spreading.

HERV Env/ receptor interactions contribute to the spreading of proteopathic seeds

To assess if HERV Env can mediate contact between donor and recipient membranes and thereby contribute to proteopathic seed spreading, the inventors overexpressed HERV-W Syncytin-1 in two HEK cell models propagating either aggregated NM-HA (HEK NM-HAagg) or aggregated Tau-GFP (HEK Tau-GFPAD) (Fig. 16a). Similar to HEK NM-HAagg cells, HEK Tau-GFPAD cells represent poor donor cells. Donors were subsequently cocultured with recipient cells expressing the respective soluble proteins. Importantly, overexpression of Myc epitope-tagged Syncytin-1 (Syn-Myc) was sufficient to increase intercellular aggregate induction in both cell culture systems (Fig. 16b, c). Expression of a Syn-Myc mutant incapable of mediating membrane fusion did not result in aggregate induction (Fig. 16b, c). The inventors reasoned that overexpression of Syncytin-1 specific receptors in recipient cells could increase aggregate induction (Fig. 16d). Indeed, ectopic expression of receptors ASCT1 (gene name SLC1A4) and ASCT2 (gene name SLC1A5) neutral amino acid transporters in recipients increased aggregate induction when recipients were cocultured with Syn-Myc expressing donor cells (Fig. 16e). By contrast, siRNA-mediated downregulation of receptor mRNAs in recipients reduced induction of protein aggregates upon coculture with Syn-Myc expressing donors (Fig. 16f-h). Next, the inventors tested if Syncytin-1 also affected aggregate induction by EV. To this end, EV from donor cell lines transiently expressing Syn- Myc were isolated and incubated with recipient cell lines overexpressing the Syncytin-1 specific receptors ASCT1/2 (genes: SLC1A4/ SLC1A5). Induction of protein aggregates in recipient cells was monitored 3 d later (Fig. 16i). Western blot analysis revealed that Syn- Myc was associated with EV fractions harboring EV markers Flotillin-1, Hsp70/72 as well as NM-HA or Tau-GFP (Fig. 16j). When added to recipient cells, Syn-Myc containing EV resulted in a significant increase in protein aggregate induction in recipient cells (Fig. 16k). In conclusion, HERV Env/ receptor interactions can contribute to the intercellular spreading of proteopathic seeds.

Materials and Methods Molecular cloning

To generate the expression vector coding for SLC1A4 or SLC1A5, the corresponding cDNA for SLC1A4 (cataloge nr. #EX-A3396-Lv213; GeneCopoeia) or SLC1A5 (cataloge nr. #EX- Z2810-Lv213; GeneCopoeia) was cloned into cataloge nr. #PB510B-1 vector (SBI) under the CMV promoter. To generate the phCMV-Syncytin-1-100UTR plasmid, Syncytin-1 cDNA tagged with a Myc epitope sequence (cataloge nr. #EX-T0264-Lv213; GeneCopoeia) was cloned into phCMV-EcoENV (Addgene #15802) using EcoRI and Xhol to replace EcoENV. The 100 bp sequence from 3 ^' -UTR of Syncytin-1 shown to enhance gene expression was amplified using primers (SEQ ID NO: 95 forward: 5’-

CCGCTCGAGAGCGGTCGTCGGCCAAC-37 SEQ ID NO: 96 reverse: 5’- GAAGATCTCCTTCCCAGCTAGGCTTAGGG-3’) and genomic DNA from MCF-7 cells as template. The sequence was cloned into phCMV-Syncytin-1 using Xhol and Bglll restriction sites. The three point mutations R314A, N315A and K316A, shown to destroy fusogenic activity, were introduced using the Q5 site-directed mutagenesis Kit (NEB).

Cell lines

MCF-7 (ATCC HTB-22) cells were cultured in MEM (Gibco) with 10% FCS, P/S, 10 nM estrogen and 0.01 mg/ml human recombinant insulin. A375 (ATCC CRL-1619) cells were cultured in DM EM (Gibco) with 10% FCS, P/S.

Brain homogenate preparation and clarification

Frozen human brain samples were homogenized in lysis buffer (for protein analysis) via Precellys® 24 (Bertin Instruments) with 1.4 mm ceramic beads at 4° C for 4 cycles 5500 rpm 20 s. To prepare 10 % (w/v) clear brain homogenate for aggregate induction, crude homogenates were centrifuged at 872 x g for 5 min at 4° C, and then the supernatants were sonicated with 50 % power for 6min. These homogenates were frozen at -80° C until use. For protein analysis, cleared supernatants were prepared by centrifugation of the crude homogenates at 15,000 x g for 15 min.

Tau aggregate induction by brain homogenate and liposomes

To induce Tau aggregation in MCF7 / A375 Tau-GFPsol cells with brain homogenates from AD patients, cells were plated on 6-well plates at 1x10 ⁶ cells/ well in 2 ml complete medium one day before. Next day, 200 pi 10 % brain homogenates and 4 mI Iipofectamine2000 were incubated for 20 min and added to recipient cells to have final 1 % brain homogenates on cells. After 3 days, cells were split and further expanded for limited dilution clone selection as previously described.

Production and transduction with lentiviral particles

HEK293T cells were cotransfected with plasmids pRSV-Rev, pMD2.VSV-G, pMDI.g/pRRE (all plasmids were published in Dull T, Zufferey R, Kelly M, Mandel RJ, Nguyen M, Trono D, Naldini L A third-generation lentivirus vector with a conditional packaging system. J Virol. 1998 Nov . 72(11 ) :8463-71 ), and pRRI.sin.PPT.hCMV.Wpre (plasmid published in Follenzi, A. and L. Naldini (2002) HIV-based vectors. Preparation and use. Methods in molecular medicine 69: 259-274) containing Tau-GFP for fluorescence tagged Tau expression or pSIH- shRNA-Syn GGCCCTCCCTTATCATATT (SEQ ID NO: 97) with the CTTCCTGTCAGA (SEQ ID NO: 98) loop sequence to silence Syncytin-1 expression, pSIH-puro-control (Addgene #26597) was used to produce control shRNA lentivirus. Supernatants were harvested and concentrated with PEG according to published protocols. MCF-7 and A375 cell lines were transduced with Tau-GFP lentivirus to produce MCF-7 and A375 Tau-GFPsol cells. MCF-7 Tau-GFPAD clones were transduced with shRNA-Syn or control lentiviruses, and selected with 2 pg/ml puromycin for 2 weeks.

Drug Treatment

To inhibit methyltransferase, MCF-7 Tau-GFPAD cells were treated with 2 mM Aza or DMSO for 4 d. Thereafter, the pretreated donor cells were cocultured with recipient HEK Tau-FRsol in the absence of the drugs for 3 d. The treatment of A375 melanoma cells with Lopinavir (10 mM; Selleckchem) and DMSO was performed for 72 h in EV-depleted medium in T175 flasks. Afterwards, the total numbers of viable cells and the viability upon drug treatments were determined using the Vi-VELLTMXR Cell Viability Analyzer (Beckman Coulter). EV were isolated from the conditioned medium via ultracentrifugation and processed for the assays as described above.

Transfection with siRNAs or plasmids

To transiently knock-down specific genes, custom-designed Silencer select siRNAs from Thermo Fisher were used. Pre-designed siRNAs were used to knock-down genes. For transfection, cells were pre-seeded on 6 well plate one d before at 2x10 ⁵ cells/well. The next day, either a final 60 nM (1:1 SLC1A4 (#s12914) / SLC1A5 (#s12918)) siRNAs (Lifetechnologies) was mixed with 1:20 diluted Lipofectamine RNAiMAX for siRNAs or 2 pi plasmid was mixed with 4 mI TranslT-2020 (Mirusbio) diluted in Opti-MEM for 30 min before addition to cells. After 1-3 d, transfected cells were harvested for aggregate induction assays, qRT-PCR or Western blot analysis. qRT-PCR

Total RNAs from cell pellets were isolated using the RNeasy Mini Kit or RNeasy Lipid Tissue Mini Kit (Qiagen). RNA concentration and quality were determined with Agilent 2100 Bioanalyzer System. RNAs were reversely transcribed to cDNA using the iScriptTM cDNA Synthesis Kit (Bio-Rad). For mRNA analysis, pre-designed TaqMan assays for human SLC1A4 (Hs00983079_m1), SLC1A5 (Hs01056542_m1), GAPDH (Hs02786624_g1) or ACTB (Hs01060665_g1) as housekeeping control were utilized with TaqManTM Gene Expression Master Mix (Thermo Fisher).

Western blotting

For Western blot analysis, protein concentrations were measured by Quick StartTM Bradford Protein assay (Bio-Rad) and proteins were separated on NuPAGE®Novex® 4-12 % Bis-Tris Protein Gels (Life Technologies) followed by transfer onto a PVDF membrane (GE Healthcare) in a wet blotting chamber. Western blot analysis was performed using rabbit anti- Flotillin-1 ab133497 (Abeam); rat anti-HA 3F10 (1:1000; Roche); mouse anti-GAPDH 6C5 (1:5000; Abeam); mouse anti-Hsp70/72 N27F3-4 (1:1000; ENZO); rabbit anti-Tau ab64193 (Abeam); rat anti-c-myc-HRP 130-092-113 (Miltenyi Biotec). The membrane was incubated with PierceTM ECL Western Blotting Substrate (Thermo Fisher Scientific) according to the manufacturer ^' s recommendations.

Image Analysis

The image analysis was performed using the CellVoyager Analysis support software. An image analysis routine was developed for single cell segmentation and aggregate identification (Yokogawa Inc.) The total number of cells was determined based on the Hoechst signal, and recipient cells were detected by their GFP/ -FR signal. Green aggregates were identified via morphology and intensity characteristics. The percentage of recipient cells with aggregated NM-GFP or Tau-FR / Tau-GFP was calculated as the number of aggregate-positive cells per total recipient cells set to 100 %. False positive induced recipient cells were detected due to the heterogeneity in GFP/FR expression of individual cells. The mean percentage of false positives determined in control recipient cells was subtracted from all samples. Of note, negative values were sometimes obtained when no induction was observed. For data presentation, the minimum range of Y Axis was set to 0.

Statistical analysis

All analyses were performed using the Prism 6.0 (GraphPad Software v.7.0c). Statistical inter-group comparisons were performed using the one-way ANOVA with a Bonferroni post test or unpaired Student’s t test p values smaller than 0.03 (*), 0.002 (**) and 0.0002 (***) were considered significant. All experiments were performed in triplicates or sextuplicates and repeated at least two times. Error bars represent the standard deviation (SD).

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