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Human Endogenous Retroviruses as Biomedicine Markers

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Virologica Sinica

Abstract

Human endogenous retroviruses (HERVs) were formed via ancient integration of exogenous retroviruses into the human genome and are considered to be viral “fossils”. The human genome is embedded with a considerable amount of HERVs, witnessing the long-term evolutionary history of the viruses and the host. Most HERVs have lost coding capability during selection but still function in terms of HERV-mediated regulation of host gene expression. In this review, we summarize the roles of HERV activation in response to viral infections and diseases, and emphasize the potential use of HERVs as biomedicine markers in the early diagnosis of diseases such as cancer, which provides a new perspective for the clinical application of HERVs.

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References

  • Aftab A, Shah AA, Hashmi AM (2016) Pathophysiological role of HERV-W in schizophrenia. J Neuropsychiatry Clin Neurosci 28:17–25

    Article  PubMed  Google Scholar 

  • Brudek T, Lühdorf P, Christensen T, Hansen HJ, Møller-Larsen A (2007) Activation of endogenous retrovirus reverse transcriptase in multiple sclerosis patient lymphocytes by inactivated HSV-1, HHV-6 and VZV. J Neuroimmunol 187:147–155

    Article  CAS  PubMed  Google Scholar 

  • Cegolon L, Salata C, Weiderpass E, Vineis P, Palù G, Mastrangelo G (2013) Human endogenous retroviruses and cancer prevention: evidence and prospects. BMC Cancer 13:4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Charvet B, Reynaud JM, Gourru-Lesimple G, Perron H, Marche PN, Horvat B (2018) Induction of proinflammatory multiple sclerosis-associated retrovirus envelope protein by human herpesvirus-6A and CD46 receptor engagement. Front Immunol 9:2803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, Hein A, Rote NS, Cope LM, Snyder A, Makarov V, Budhu S, Slamon DJ, Wolchok JD, Pardoll DM, Beckmann MW, Zahnow CA, Merghoub T, Chan TA, Baylin SB, Strick R (2015) Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162:974–986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chignola R, Sega M, Molesini B, Baruzzi A, Stella S, Milotti E (2019) Collective radioresistance of T47D breast carcinoma cells is mediated by a Syncytin-1 homologous protein. PLoS ONE 14:e0206713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Contreras-Galindo R, López P, Vélez R, Yamamura Y (2007) HIV-1 infection increases the expression of human endogenous retroviruses type K (HERV-K) in vitro. AIDS Res Hum Retroviruses 23:116–122

    Article  CAS  PubMed  Google Scholar 

  • Dembny P, Newman AG, Singh M, Hinz M, Szczepek M, Kruger C, Adalbert R, Dzaye O, Trimbuch T, Wallach T, Kleinau G, Derkow K, Richard BC, Schipke C, Scheidereit C, Stachelscheid H, Golenbock D, Peters O, Coleman M, Heppner FL, Scheerer P, Tarabykin V, Ruprecht K, Izsvak Z, Mayer J, Lehnardt S (2020) Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors. JCI Insight 5:e131093

    Article  PubMed Central  Google Scholar 

  • Douville R, Liu J, Rothstein J, Nath A (2011) Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis. Ann Neurol 69:141–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eirew P, Steif A, Khattra J, Ha G, Yap D, Farahani H, Gelmon K, Chia S, Mar C, Wan A, Laks E, Biele J, Shumansky K, Rosner J, McPherson A, Nielsen C, Roth AJ, Lefebvre C, Bashashati A, de Souza C, Siu C, Aniba R, Brimhall J, Oloumi A, Osako T, Bruna A, Sandoval JL, Algara T, Greenwood W, Leung K, Cheng H, Xue H, Wang Y, Lin D, Mungall AJ, Moore R, Zhao Y, Lorette J, Nguyen L, Huntsman D, Eaves CJ, Hansen C, Marra MA, Caldas C, Shah SP, Aparicio S (2015) Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution. Nature 518:422–426

    Article  CAS  PubMed  Google Scholar 

  • Elsässer SJ, Noh KM, Diaz N, Allis CD, Banaszynski LA (2015) Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells. Nature 522:240–244

    Article  PubMed  PubMed Central  Google Scholar 

  • Faucard R, Madeira A, Gehin N, Authier FJ, Panaite PA, Lesage C, Burgelin I, Bertel M, Bernard C, Curtin F, Lang AB, Steck AJ, Perron H, Kuntzer T, Créange A (2016) Human endogenous retrovirus and neuroinflammation in chronic inflammatory demyelinating polyradiculoneuropathy. EBioMedicine 6:190–198

    Article  PubMed  PubMed Central  Google Scholar 

  • Galli UM, Sauter M, Lecher B, Maurer S, Herbst H, Roemer K, Mueller-Lantzsch N (2005) Human endogenous retrovirus rec interferes with germ cell development in mice and may cause carcinoma in situ, the predecessor lesion of germ cell tumors. Oncogene 24:3223–3228

    Article  CAS  PubMed  Google Scholar 

  • Gimenez J, Montgiraud C, Pichon JP, Bonnaud B, Arsac M, Ruel K, Bouton O, Mallet F (2010) Custom human endogenous retroviruses dedicated microarray identifies self-induced HERV-W family elements reactivated in testicular cancer upon methylation control. Nucl Acids Res 38:2229–2246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gude NM, Roberts CT, Kalionis B, King RG (2004) Growth and function of the normal human placenta. Thromb Res 114:397–407

    Article  CAS  PubMed  Google Scholar 

  • Hanna CW, Pérez-Palacios R, Gahurova L, Schubert M, Krueger F, Biggins L, Andrews S, Colomé-Tatché M, Bourc’his D, Dean W, Kelsey G (2019) Endogenous retroviral insertions drive non-canonical imprinting in extra-embryonic tissues. Genome Biol 20:225

    Article  PubMed  PubMed Central  Google Scholar 

  • Henzy JE, Johnson WE (2013) Pushing the endogenous envelope. Philos Trans R Soc Lond B Biol Sci 368:20120506

    Article  PubMed  PubMed Central  Google Scholar 

  • Hoang DT, Chernomor O, von Haeseler A, Minh BQ, Vinh LS (2018) UFBoot2: improving the ultrafast bootstrap approximation. Mol Biol Evol 35:518–522

    Article  CAS  PubMed  Google Scholar 

  • Hu T, Zhu X, Pi W, Yu M, Shi H, Tuan D (2017) Hypermethylated LTR retrotransposon exhibits enhancer activity. Epigenetics 12:226–237

    Article  PubMed  PubMed Central  Google Scholar 

  • Huang W, Li S, Hu Y, Yu H, Luo F, Zhang Q, Zhu F (2011) Implication of the env gene of the human endogenous retrovirus W family in the expression of BDNF and DRD3 and development of recent-onset schizophrenia. Schizophr Bull 37:988–1000

    Article  PubMed  Google Scholar 

  • Huang Q, Chen H, Li J, Oliver M, Ma X, Byck D, Gao Y, Jiang SW (2014) Epigenetic and non-epigenetic regulation of syncytin-1 expression in human placenta and cancer tissues. Cell Signal 26:648–656

    Article  CAS  PubMed  Google Scholar 

  • Johansson EM, Bouchet D, Tamouza R, Ellul P, Morr AS, Avignone E, Germi R, Leboyer M, Perron H, Groc L (2020) Human endogenous retroviral protein triggers deficit in glutamate synapse maturation and behaviors associated with psychosis. Sci Adv 6:eabc0708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnston JB, Silva C, Holden J, Warren KG, Clark AW, Power C (2001) Monocyte activation and differentiation augment human endogenous retrovirus expression: implications for inflammatory brain diseases. Ann Neurol 50:434–442

    Article  CAS  PubMed  Google Scholar 

  • Kassiotis G (2014) Endogenous retroviruses and the development of cancer. J Immunol 192:1343–1349

    Article  CAS  PubMed  Google Scholar 

  • Katsura Y, Asai S (2019) Evolutionary medicine of retroviruses in the human genome. Am J Med Sci 358:384–388

    Article  PubMed  PubMed Central  Google Scholar 

  • Kelleher CA, Wilkinson DA, Freeman JD, Mager DL, Gelfand EW (1996) Expression of novel-transposon-containing mRNAs in human T cells. J Gen Virol 77:1101–1110

    Article  CAS  PubMed  Google Scholar 

  • Kremer D, Gruchot J, Weyers V, Oldemeier L, Gottle P, Healy L, Ho Jang J, Kang TXY, Volsko C, Dutta R, Trapp BD, Perron H, Hartung HP, Kury P (2019) pHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis. Proc Natl Acad Sci U S A 116:15216–15225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kury P, Nath A, Creange A, Dolei A, Marche P, Gold J, Giovannoni G, Hartung HP, Perron H (2018) Human endogenous retroviruses in neurological diseases. Trends Mol Med 24:379–394

    Article  PubMed  PubMed Central  Google Scholar 

  • Lamprecht B, Walter K, Kreher S, Kumar R, Hummel M, Lenze D, Köchert K, Bouhlel MA, Richter J, Soler E, Stadhouders R, Jöhrens K, Wurster KD, Callen DF, Harte MF, Giefing M, Barlow R, Stein H, Anagnostopoulos I, Janz M, Cockerill PN, Siebert R, Dörken B, Bonifer C, Mathas S (2010) Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma. Nat Med 16:571–579

    Article  CAS  PubMed  Google Scholar 

  • Lee JR, Ahn K, Kim YJ, Jung YD, Kim HS (2012) Radiation-induced human endogenous retrovirus (HERV)-R env gene expression by epigenetic control. Radiat Res 178:379–384

    Article  CAS  PubMed  Google Scholar 

  • Li F, Nellaker C, Sabunciyan S, Yolken RH, Jones-Brando L, Johansson AS, Owe-Larsson B, Karlsson H (2014) Transcriptional derepression of the ERVWE1 locus following influenza A virus infection. J Virol 88:4328–4337

    Article  PubMed  PubMed Central  Google Scholar 

  • Li W, Lee MH, Henderson L, Tyagi R, Bachani M, Steiner J, Campanac E, Hoffman DA, von Geldern G, Johnson K, Maric D, Morris HD, Lentz M, Pak K, Mammen A, Ostrow L, Rothstein J, Nath A (2015) Human endogenous retrovirus-K contributes to motor neuron disease. Sci Transl Med 7:307ra153

    Article  PubMed  PubMed Central  Google Scholar 

  • Lin EH, Salon C, Brambilla E, Lavillette D, Szecsi J, Cosset FL, Coll JL (2010) Fusogenic membrane glycoproteins induce syncytia formation and death in vitro and in vivo: a potential therapy agent for lung cancer. Cancer Gene Ther 17:256–265

    Article  CAS  PubMed  Google Scholar 

  • Liu C, Chen Y, Li S, Yu H, Zeng J, Wang X, Zhu F (2013) Activation of elements in HERV-W family by caffeine and aspirin. Virus Genes 47:219–227

    Article  CAS  PubMed  Google Scholar 

  • Liu C, Liu L, Wang X, Liu Y, Wang M, Zhu F (2017) HBV X protein induces overexpression of HERV-W env through NF-κB in HepG2 cells. Virus Genes 53:797–806

    Article  CAS  PubMed  Google Scholar 

  • Mameli G, Poddighe L, Astone V, Delogu G, Arru G, Sotgiu S, Serra C, Dolei A (2009) Novel reliable real-time PCR for differential detection of MSRVenv and syncytin-1 in RNA and DNA from patients with multiple sclerosis. J Virol Methods 161:98–106

    Article  CAS  PubMed  Google Scholar 

  • Mameli G, Poddighe L, Mei A, Uleri E, Sotgiu S, Serra C, Manetti R, Dolei A (2012) Expression and activation by Epstein Barr virus of human endogenous retroviruses-W in blood cells and astrocytes: inference for multiple sclerosis. PLoS ONE 7:e44991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mameli G, Madeddu G, Mei A, Uleri E, Poddighe L, Delogu LG, Maida I, Babudieri S, Serra C, Manetti R, Mura MS, Dolei A (2013) Activation of MSRV-type endogenous retroviruses during infectious mononucleosis and Epstein–Barr virus latency: the missing link with multiple sclerosis? PLoS ONE 8:e78474

    Article  PubMed  PubMed Central  Google Scholar 

  • Menendez L, Benigno BB, McDonald JF (2004) L1 and HERV-W retrotransposons are hypomethylated in human ovarian carcinomas. Mol Cancer 3:12

    Article  PubMed  PubMed Central  Google Scholar 

  • Mi S, Lee X, Li X, Veldman GM, Finnerty H, Racie L, LaVallie E, Tang XY, Edouard P, Howes S, Keith JC Jr, McCoy JM (2000) Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403:785–789

    Article  CAS  PubMed  Google Scholar 

  • Minh BQ, Schmidt HA, Chernomor O, Schrempf D, Woodhams MD, von Haeseler A, Lanfear R (2020) IQ-TREE 2: new models and efficient methods for phylogenetic inference in the genomic era. Mol Biol Evol 37:1530–1534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nanus DM, Gudas LJ (2016) The tale of two hypoxia-inducible factors in renal cell carcinoma. Eur Urol 69:658–659

    Article  CAS  PubMed  Google Scholar 

  • Perron H, Mekaoui L, Bernard C, Veas F, Stefas I, Leboyer M (2008) Endogenous retrovirus type W GAG and envelope protein antigenemia in serum of schizophrenic patients. Biol Psychiatry 64:1019–1023

    Article  CAS  PubMed  Google Scholar 

  • Perron H, Germi R, Bernard C, Garcia-Montojo M, Deluen C, Farinelli L, Faucard R, Veas F, Stefas I, Fabriek BO, Van-Horssen J, Van-der-Valk P, Gerdil C, Mancuso R, Saresella M, Clerici M, Marcel S, Creange A, Cavaretta R, Caputo D, Arru G, Morand P, Lang AB, Sotgiu S, Ruprecht K, Rieckmann P, Villoslada P, Chofflon M, Boucraut J, Pelletier J, Hartung HP (2012) Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease. Mult Scler 18:1721–1736

    Article  PubMed  PubMed Central  Google Scholar 

  • Reis BS, Jungbluth AA, Frosina D, Holz M, Ritter E, Nakayama E, Ishida T, Obata Y, Carver B, Scher H, Scardino PT, Slovin S, Subudhi SK, Reuter VE, Savage C, Allison JP, Melamed J, Jäger E, Ritter G, Old LJ, Gnjatic S (2013) Prostate cancer progression correlates with increased humoral immune response to a human endogenous retrovirus GAG protein. Clin Cancer Res 19:6112–6125

    Article  CAS  PubMed  Google Scholar 

  • Ruprecht K, Mayer J, Sauter M, Roemer K, Mueller-Lantzsch N (2008) Endogenous retroviruses and cancer. Cell Mol Life Sci 65:3366–3382

    Article  CAS  PubMed  Google Scholar 

  • Siebenthall KT, Miller CP, Vierstra JD, Mathieu J, Tretiakova M, Reynolds A, Sandstrom R, Rynes E, Haugen E, Johnson A, Nelson J, Bates D, Diegel M, Dunn D, Frerker M, Buckley M, Kaul R, Zheng Y, Himmelfarb J, Ruohola-Baker H, Akilesh S (2019) Integrated epigenomic profiling reveals endogenous retrovirus reactivation in renal cell carcinoma. EBioMedicine 41:427–442

    Article  PubMed  PubMed Central  Google Scholar 

  • Singer GA, Wu J, Yan P, Plass C, Huang TH, Davuluri RV (2008) Genome-wide analysis of alternative promoters of human genes using a custom promoter tiling array. BMC Genom 9:349

    Article  Google Scholar 

  • Smith CC, Beckermann KE, Bortone DS, De Cubas AA, Bixby LM, Lee SJ, Panda A, Ganesan S, Bhanot G, Wallen EM, Milowsky MI, Kim WY, Rathmell WK, Swanstrom R, Parker JS, Serody JS, Selitsky SR, Vincent BG (2018) Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma. J Clin Invest 128:4804–4820

    Article  PubMed  PubMed Central  Google Scholar 

  • Stoye JP (2012) Studies of endogenous retroviruses reveal a continuing evolutionary saga. Nat Rev Microbiol 10:395–406

    Article  CAS  PubMed  Google Scholar 

  • Subramanian RP, Wildschutte JH, Russo C, Coffin JM (2011) Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses. Retrovirology 8:90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tu X, Li S, Zhao L, Xiao R, Wang X, Zhu F (2017) Human leukemia antigen-A*0201-restricted epitopes of human endogenous retrovirus W family envelope (HERV-W env) induce strong cytotoxic T lymphocyte responses. Virol Sin 32:280–289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Türkmen S, Riehn M, Klopocki E, Molkentin M, Reinhardt R, Burmeister T (2011) A BACH2-BCL2L1 fusion gene resulting from a t(6;20)(q15;q11.2) chromosomal translocation in the lymphoma cell line BLUE-1. Genes Chromosomes Cancer 50:389–396

    Article  PubMed  Google Scholar 

  • Vargiu L, Rodriguez-Tome P, Sperber GO, Cadeddu M, Grandi N, Blikstad V, Tramontano E, Blomberg J (2016) Classification and characterization of human endogenous retroviruses; mosaic forms are common. Retrovirology 13:7

    Article  PubMed  PubMed Central  Google Scholar 

  • Walsh CP, Chaillet JR, Bestor TH (1998) Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet 20:116–117

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Huang J, Zhu F (2018a) Human Endogenous retroviral envelope protein syncytin-1 and inflammatory abnormalities in neuropsychological diseases. Front Psychiatry 9:422

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang X, Liu Z, Wang P, Li S, Zeng J, Tu X, Yan Q, Xiao Z, Pan M, Zhu F (2018b) Syncytin-1, an endogenous retroviral protein, triggers the activation of CRP via TLR3 signal cascade in glial cells. Brain Behav Immun 67:324–334

    Article  CAS  PubMed  Google Scholar 

  • Xiao R, Li S, Cao Q, Wang X, Yan Q, Tu X, Zhu Y, Zhu F (2017) Human endogenous retrovirus W env increases nitric oxide production and enhances the migration ability of microglia by regulating the expression of inducible nitric oxide synthase. Virol Sin 32:216–225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu H, Liu T, Zhao Z, Chen Y, Zeng J, Liu S, Zhu F (2014) Mutations in 3′-long terminal repeat of HERV-W family in chromosome 7 upregulate syncytin-1 expression in urothelial cell carcinoma of the bladder through interacting with c-Myb. Oncogene 33:3947–3958

    Article  CAS  PubMed  Google Scholar 

  • Zare M, Mostafaei S, Ahmadi A, Azimzadeh Jamalkandi S, Abedini A, Esfahani-Monfared Z, Dorostkar R, Saadati M (2018) Human endogenous retrovirus env genes: potential blood biomarkers in lung cancer. Microb Pathog 115:189–193

    Article  CAS  PubMed  Google Scholar 

  • Zhang M, Liang JQ, Zheng S (2019) Expressional activation and functional roles of human endogenous retroviruses in cancers. Rev Med Virol 29:e2025

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported by the National Science and Technology Major Project (Grant No. 2018ZX10301101), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA13010500) and the CAS Pioneer Hundred Talents Program to JC.

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  1. Yuhe Song and Xiang Li contributed equally to this work.

Authors and Affiliations

  1. School of Life Sciences, Shanghai University, Shanghai, 200444, China

    Yuhe Song

  2. CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Shanghai, 200031, China

    Yuhe Song, Xiang Li, Xiaoman Wei & Jie Cui

  3. University of Chinese Academy of Sciences, Beijing, 100049, China

    Xiang Li & Xiaoman Wei

  4. CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China

    Xiaoman Wei

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  1. Yuhe Song
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Song, Y., Li, X., Wei, X. et al. Human Endogenous Retroviruses as Biomedicine Markers. Virol. Sin. 36, 852–858 (2021). https://doi.org/10.1007/s12250-021-00387-7

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