HERVs Role in the Pathogenesis, Diagnosis or Prognosis of Aging
Diseases: A Systematic Review

Paula      Prieto-Oliveira
Abstract

Introduction: HERVs are human endogenous retroviruses, which represent about 8% of the human genome, and have various physiological functions, especially in pregnancy, embryo development and placenta formation. However, their involvement in diseases is not well defined. Some studies have observed changes in HERV expression according to age.
Objective: Therefore, the aim of this systematic review was to analyze their role in pathogenesis and usage as diagnosis or prognosis biomarkers in aging disorders.
Methods: In this study, a search on the Pubmed interface was performed for papers published from January 1953 to June 1^st, 2021.
Results: 45 articles have been included, which matched the eligibility criteria and evaluated the following diseases: breast cancer, prostate cancer, amyotrophic lateral sclerosis (ALS), osteoarthritis, Alzheimer's disease, immuno-senescence, cognitive impairment, cataract, glaucoma and hypertension.
Conclusion: In conclusion, the results suggested that HERVs play a role in the pathogenesis and can be used as biomarkers for the diagnosis or prognosis of aging disorders.
Keywords: HERVs, ERVs, endogenous retroviruses, aging, senescence, disease.
[1]
Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature  2001; 409(6822): 860-921.
 [http://dx.doi.org/10.1038/35057062] [PMID: 11237011]

[2]
Hayward A, Cornwallis CK, Jern P. Pan-vertebrate comparative genomics unmasks retrovirus macroevolution. Proc Natl Acad Sci USA  2015; 112(2): 464-9.
 [http://dx.doi.org/10.1073/pnas.1414980112] [PMID: 25535393]

[3]
Löwer R, Löwer J, Tondera-Koch C, Kurth R. A general method for the identification of transcribed retrovirus sequences (R-U5 PCR) reveals the expression of the human endogenous retrovirus loci HERV-H and HERV-K in teratocarcinoma cells. Virology  1993; 192(2): 501-11.
 [http://dx.doi.org/10.1006/viro.1993.1066] [PMID: 8421897]

[4]
Magin C, Löwer R, Löwer J. cORF and RcRE, the Rev/Rex and RRE/RxRE homologues of the human endogenous retrovirus family HTDV/HERV-K. J Virol  1999; 73(11): 9496-507.
 [http://dx.doi.org/10.1128/JVI.73.11.9496-9507.1999] [PMID: 10516058]

[5]
Heidmann O, Heidmann T. Retrotransposition of a mouse IAP sequence tagged with an indicator gene. Cell  1991; 64(1): 159-70.
 [http://dx.doi.org/10.1016/0092-8674(91)90217-M] [PMID: 1846087]

[6]
Bannert N, Kurth R. The evolutionary dynamics of human endogenous retroviral families. Annu Rev Genomics Hum Genet  2006; 7(1): 149-73.
 [http://dx.doi.org/10.1146/annurev.genom.7.080505.115700] [PMID: 16722807]

[7]
Grandi N, Tramontano E. Human endogenous retroviruses are ancient acquired elements still shaping innate immune responses. Front Immunol  2018; 9: 2039.
 [http://dx.doi.org/10.3389/fimmu.2018.02039] [PMID: 30250470]

[8]
Löwer R, Boller K, Hasenmaier B, et al. Identification of human endogenous retroviruses with complex mRNA expression and particle formation. Proc Natl Acad Sci USA  1993; 90(10): 4480-4.
 [http://dx.doi.org/10.1073/pnas.90.10.4480] [PMID: 8506289]

[9]
Yang J, Bogerd HP, Peng S, Wiegand H, Truant R, Cullen BR. An ancient family of human endogenous retroviruses encodes a functional homolog of the HIV-1 Rev protein. Proc Natl Acad Sci USA  1999; 96(23): 13404-8.
 [http://dx.doi.org/10.1073/pnas.96.23.13404] [PMID: 10557333]

[10]
Armbruester V, Sauter M, Roemer K, et al. Np9 protein of human endogenous retrovirus K interacts with ligand of numb protein X. J Virol  2004; 78(19): 10310-9.
 [http://dx.doi.org/10.1128/JVI.78.19.10310-10319.2004] [PMID: 15367597]

[11]
Denne M, Sauter M, Armbruester V, Licht JD, Roemer K, Mueller-Lantzsch N. Physical and functional interactions of human endogenous retrovirus proteins Np9 and rec with the promyelocytic leukemia zinc finger protein. J Virol  2007; 81(11): 5607-16.
 [http://dx.doi.org/10.1128/JVI.02771-06] [PMID: 17360752]

[12]
Terzian C, Pélisson A, Bucheton A. Evolution and phylogeny of insect endogenous retroviruses. BMC Evol Biol  2001; 1(1): 3.
 [http://dx.doi.org/10.1186/1471-2148-1-3] [PMID: 11591216]

[13]
Song SU, Gerasimova T, Kurkulos M, Boeke JD, Corces VG. An env-like protein encoded by a Drosophila retroelement: Evidence that gypsy is an infectious retrovirus. Genes Dev  1994; 8(17): 2046-57.
 [http://dx.doi.org/10.1101/gad.8.17.2046] [PMID: 7958877]

[14]
Kim A, Terzian C, Santamaria P, Pélisson A, Purd’homme N, Bucheton A. Retroviruses in invertebrates: The gypsy retrotransposon is apparently an infectious retrovirus of Drosophila melanogaster. Proc Natl Acad Sci USA  1994; 91(4): 1285-9.
 [http://dx.doi.org/10.1073/pnas.91.4.1285] [PMID: 8108403]

[15]
Marlor RL, Parkhurst SM, Corces VG. The Drosophila melanogaster gypsy transposable element encodes putative gene products homologous to retroviral proteins. Mol Cell Biol  1986; 6(4): 1129-34.
 [PMID: 3023871]

[16]
Johnson WE, Coffin JM. Constructing primate phylogenies from ancient retrovirus sequences. Proc Natl Acad Sci USA  1999; 96(18): 10254-60.
 [http://dx.doi.org/10.1073/pnas.96.18.10254] [PMID: 10468595]

[17]
Tristem M. Identification and characterization of novel human endogenous retrovirus families by phylogenetic screening of the human genome mapping project database. J Virol  2000; 74(8): 3715-30.
 [http://dx.doi.org/10.1128/JVI.74.8.3715-3730.2000] [PMID: 10729147]

[18]
de Parseval N, Lazar V, Casella JF, Benit L, Heidmann T. Survey of human genes of retroviral origin: Identification and transcriptome of the genes with coding capacity for complete envelope proteins. J Virol  2003; 77(19): 10414-22.
 [http://dx.doi.org/10.1128/JVI.77.19.10414-10422.2003] [PMID: 12970426]

[19]
Villesen P, Aagaard L, Wiuf C, Pedersen FS. Identification of endogenous retroviral reading frames in the human genome. Retrovirology  2004; 1(1): 32.
 [http://dx.doi.org/10.1186/1742-4690-1-32] [PMID: 15476554]

[20]
Vargiu L, Rodriguez-Tomé P, Sperber GO, et al. Classification and characterization of human endogenous retroviruses; mosaic forms are common. Retrovirology  2016; 13(1): 7.
 [http://dx.doi.org/10.1186/s12977-015-0232-y] [PMID: 26800882]

[21]
Cohen M, Larsson E. Human endogenous retroviruses. BioEssays  1988; 9(6): 191-6.
 [http://dx.doi.org/10.1002/bies.950090603] [PMID: 2853942]

[22]
Hughes JF, Coffin JM. Evidence for genomic rearrangements mediated by human endogenous retroviruses during primate evolution. Nat Genet  2001; 29(4): 487-9.
 [http://dx.doi.org/10.1038/ng775] [PMID: 11704760]

[23]
Subramanian RP, Wildschutte JH, Russo C, Coffin JM. Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses. Retrovirology  2011; 8(1): 90.
 [http://dx.doi.org/10.1186/1742-4690-8-90] [PMID: 22067224]

[24]
Goering W, Schmitt K, Dostert M, et al. Human endogenous retrovirus HERV-K(HML-2) activity in prostate cancer is dominated by a few loci. Prostate  2015; 75(16): 1958-71.
 [http://dx.doi.org/10.1002/pros.23095] [PMID: 26384005]

[25]
Mayer J, Blomberg J, Seal RL. A revised nomenclature for transcribed human endogenous retroviral loci. Mob DNA  2011; 2(1): 7.
 [http://dx.doi.org/10.1186/1759-8753-2-7] [PMID: 21542922]

[26]
Blomberg J, Benachenhou F, Blikstad V, Sperber G, Mayer J. Classification and nomenclature of endogenous retroviral sequences (ERVs): Problems and recommendations. Gene  2009; 448(2): 115-23.
 [http://dx.doi.org/10.1016/j.gene.2009.06.007] [PMID: 19540319]

[27]
Hurst TP, Magiorkinis G. Epigenetic control of human endogenous retrovirus expression: Focus on regulation of Long-Terminal Repeats (LTRs). Viruses  2017; 9(6): 130.
 [http://dx.doi.org/10.3390/v9060130] [PMID: 28561791]

[28]
Blond JL, Lavillette D, Cheynet V, et al. An envelope glycoprotein of the human endogenous retrovirus HERV-W is expressed in the human placenta and fuses cells expressing the type D mammalian retrovirus receptor. J Virol  2000; 74(7): 3321-9.
 [http://dx.doi.org/10.1128/JVI.74.7.3321-3329.2000] [PMID: 10708449]

[29]
Malassiné A, Handschuh K, Tsatsaris V, et al. Expression of HERV-W Env glycoprotein (syncytin) in the extravillous trophoblast of first trimester human placenta. Placenta  2005; 26(7): 556-62.
 [http://dx.doi.org/10.1016/j.placenta.2004.09.002] [PMID: 15993705]

[30]
Blaise S, de Parseval N, Bénit L, Heidmann T. Genomewide screening for fusogenic human endogenous retrovirus envelopes identifies syncytin 2, a gene conserved on primate evolution. Proc Natl Acad Sci USA  2003; 100(22): 13013-8.
 [http://dx.doi.org/10.1073/pnas.2132646100] [PMID: 14557543]

[31]
Kato N, Pfeifer-Ohlsson S, Kato M, et al. Tissue-specific expression of human provirus ERV3 mRNA in human placenta: Two of the three ERV3 mRNAs contain human cellular sequences. J Virol  1987; 61(7): 2182-91.
 [http://dx.doi.org/10.1128/jvi.61.7.2182-2191.1987] [PMID: 2884330]

[32]
Beyer U, Moll-Rocek J, Moll UM, Dobbelstein M. Endogenous retrovirus drives hitherto unknown proapoptotic p63 isoforms in the male germ line of humans and great apes. Proc Natl Acad Sci USA  2011; 108(9): 3624-9.
 [http://dx.doi.org/10.1073/pnas.1016201108] [PMID: 21300884]

[33]
Wang J, Xie G, Singh M, et al. Primate-specific endogenous retrovirus-driven transcription defines naive-like stem cells. Nature  2014; 516(7531): 405-9.
 [http://dx.doi.org/10.1038/nature13804] [PMID: 25317556]

[34]
Pontis J, Planet E, Offner S, et al. Hominoid-specific transposable elements and KZFPs facilitate human embryonic genome activation and control transcription in naive human ESCs. Cell Stem Cell  2019; 24(5): 724-735.e5.
 [http://dx.doi.org/10.1016/j.stem.2019.03.012] [PMID: 31006620]

[35]
Mi S, Lee X, Li X, et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature  2000; 403(6771): 785-9.
 [http://dx.doi.org/10.1038/35001608] [PMID: 10693809]

[36]
Frendo JL, Olivier D, Cheynet V, et al. Direct involvement of HERV-W Env glycoprotein in human trophoblast cell fusion and differentiation. Mol Cell Biol  2003; 23(10): 3566-74.
 [http://dx.doi.org/10.1128/MCB.23.10.3566-3574.2003] [PMID: 12724415]

[37]
Liang CY, Wang LJ, Chen CP, Chen LF, Chen YH, Chen H. GCM1 regulation of the expression of syncytin 2 and its cognate receptor MFSD2A in human placenta. Biol Reprod  2010; 83(3): 387-95.
 [http://dx.doi.org/10.1095/biolreprod.110.083915] [PMID: 20484742]

[38]
Rolland A, Jouvin-Marche E, Viret C, Faure M, Perron H, Marche PN. The envelope protein of a human endogenous retrovirus-W family activates innate immunity through CD14/TLR4 and promotes Th1-like responses. J Immunol  2006; 176(12): 7636-44.
 [http://dx.doi.org/10.4049/jimmunol.176.12.7636] [PMID: 16751411]

[39]
Ponferrada VG, Mauck BS, Wooley DP. The envelope glycoprotein of human endogenous retrovirus HERV-W induces cellular resistance to spleen necrosis virus. Arch Virol  2003; 148(4): 659-75.
 [http://dx.doi.org/10.1007/s00705-002-0960-x] [PMID: 12664292]

[40]
van Horssen J, van der Pol S, Nijland P, Amor S, Perron H. Human endogenous retrovirus W in brain lesions: Rationale for targeted therapy in multiple sclerosis. Mult Scler Relat Disord  2016; 8: 11-8.
 [http://dx.doi.org/10.1016/j.msard.2016.04.006] [PMID: 27456869]

[41]
Ramasamy R, Joseph B, Whittall T. Potential molecular mimicry between the human endogenous retrovirus W family envelope proteins and myelin proteins in multiple sclerosis. Immunol Lett  2017; 183: 79-85.
 [http://dx.doi.org/10.1016/j.imlet.2017.02.003] [PMID: 28189601]

[42]
Garcia-Montojo M, Rodriguez-Martin E, Ramos-Mozo P, et al. Syncytin-1/HERV-W envelope is an early activation marker of leukocytes and is upregulated in multiple sclerosis patients. Eur J Immunol  2020; 50(5): 685-94.
 [http://dx.doi.org/10.1002/eji.201948423] [PMID: 32012247]

[43]
Ogasawara H, Naito T, Kaneko H, et al. Quantitative analyses of messenger RNA of human endogenous retrovirus in patients with systemic lupus erythematosus. J Rheumatol  2001; 28(3): 533-8.
 [PMID: 11296954]

[44]
Wu Z, Mei X, Zhao D, et al. DNA methylation modulates HERV-E expression in CD4+ T cells from systemic lupus erythematosus patients. J Dermatol Sci  2015; 77(2): 110-6.
 [http://dx.doi.org/10.1016/j.jdermsci.2014.12.004] [PMID: 25595738]

[45]
Iñiguez LP, de Mulder Rougvie M, Stearrett N, et al. Transcriptomic analysis of human endogenous retroviruses in systemic lupus erythematosus. Proc Natl Acad Sci USA  2019; 116(43): 21350-1.
 [http://dx.doi.org/10.1073/pnas.1907705116] [PMID: 31594853]

[46]
Freimanis G, Hooley P, Ejtehadi HD, et al. A role for human endogenous retrovirus-K (HML-2) in rheumatoid arthritis: Investigating mechanisms of pathogenesis. Clin Exp Immunol  2010; 160(3): 340-7.
 [http://dx.doi.org/10.1111/j.1365-2249.2010.04110.x] [PMID: 20345981]

[47]
Mameli G, Erre GL, Caggiu E, et al. Identification of a HERVK env surface peptide highly recognized in Rheumatoid Arthritis (RA) patients: A cross-sectional case-control study. Clin Exp Immunol  2017; 189(1): 127-31.
 [http://dx.doi.org/10.1111/cei.12964] [PMID: 28324619]

[48]
Pérot P, Mullins CS, Naville M, et al. Expression of young HERV-H loci in the course of colorectal carcinoma and correlation with molecular subtypes. Oncotarget  2015; 6(37): 40095-111.
 [http://dx.doi.org/10.18632/oncotarget.5539] [PMID: 26517682]

[49]
Yu H, Liu T, Zhao Z, et al. 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  2014; 33(30): 3947-58.
 [http://dx.doi.org/10.1038/onc.2013.366] [PMID: 24013223]

[50]
Ma W, Hong Z, Liu H, et al. Human endogenous retroviruses-K (HML-2) expression is correlated with prognosis and progress of hepatocellular carcinoma. BioMed Res Int  2016; 2016: 8201642.
 [http://dx.doi.org/10.1155/2016/8201642] [PMID: 28070518]

[51]
Iramaneerat K, Rattanatunyong P, Khemapech N, Triratanachat S, Mutirangura A. HERV-K hypomethylation in ovarian clear cell carcinoma is associated with a poor prognosis and platinum resistance. Int J Gynecol Cancer  2011; 21(1): 51-7.
 [http://dx.doi.org/10.1097/IGC.0b013e3182021c1a] [PMID: 21330831]

[52]
Cardelli M, Doorn RV, Larcher L, et al. Association of HERVK and LINE-1 hypomethylation with reduced disease-free survival in melanoma patients. Epigenomics  2020; 12(19): 1689-706.
 [http://dx.doi.org/10.2217/epi-2020-0127] [PMID: 33125285]

[53]
Argaw-Denboba A, Balestrieri E, Serafino A, et al. HERV-K activation is strictly required to sustain CD133+ melanoma cells with stemness features. J Exp Clin Cancer Res  2017; 36(1): 20.
 [http://dx.doi.org/10.1186/s13046-016-0485-x] [PMID: 28125999]

[54]
Schmitt K, Reichrath J, Roesch A, Meese E, Mayer J. Transcriptional profiling of human endogenous retrovirus group HERV-K(HML-2) loci in melanoma. Genome Biol Evol  2013; 5(2): 307-28.
 [http://dx.doi.org/10.1093/gbe/evt010] [PMID: 23338945]

[55]
Dai L, Del Valle L, Miley W, et al. Transactivation of human endogenous retrovirus K (HERV-K) by KSHV promotes Kaposi’s sarcoma development. Oncogene  2018; 37(33): 4534-45.
 [http://dx.doi.org/10.1038/s41388-018-0282-4] [PMID: 29743595]

[56]
Jintaridth P, Mutirangura A. Distinctive patterns of age-dependent hypomethylation in interspersed repetitive sequences. Physiol Genomics  2010; 41(2): 194-200.
 [http://dx.doi.org/10.1152/physiolgenomics.00146.2009] [PMID: 20145203]

[57]
Balestrieri E, Pica F, Matteucci C, et al. Transcriptional activity of human endogenous retroviruses in human peripheral blood mononuclear cells. BioMed Res Int  2015; 2015: 164529.
 [http://dx.doi.org/10.1155/2015/164529] [PMID: 25734056]

[58]
Min B, Jeon K, Park JS, Kang YK. Demethylation and derepression of genomic retroelements in the skeletal muscles of aged mice. Aging Cell  2019; 18(6): e13042.
 [http://dx.doi.org/10.1111/acel.13042] [PMID: 31560164]

[59]
Singhal RP, Mays-Hoopes LL, Eichhorn GL. DNA methylation in aging of mice. Mech Ageing Dev  1987; 41(3): 199-210.
 [http://dx.doi.org/10.1016/0047-6374(87)90040-6] [PMID: 3431172]

[60]
Wilson VL, Smith RA, Ma S, Cutler RG. Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem  1987; 262(21): 9948-51.
 [http://dx.doi.org/10.1016/S0021-9258(18)61057-9] [PMID: 3611071]

[61]
Drinkwater RD, Blake TJ, Morley AA, Turner DR. Human lymphocytes aged in vivo have reduced levels of methylation in transcriptionally active and inactive DNA. Mutation Research/DNAging  1989; 219(1): 29-37.

[62]
Golbus J, Palella TD, Richardson BC. Quantitative changes in T cell DNA methylation occur during differentiation and ageing. Eur J Immunol  1990; 20(8): 1869-72.
 [http://dx.doi.org/10.1002/eji.1830200836] [PMID: 2209694]

[63]
Fuke C, Shimabukuro M, Petronis A, et al. Age related changes in 5-methylcytosine content in human peripheral leukocytes and placentas: An HPLC-based study. Ann Hum Genet  2004; 68(Pt 3): 196-204.
 [http://dx.doi.org/10.1046/j.1529-8817.2004.00081.x] [PMID: 15180700]

[64]
Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ  2021; 372: n71.
 [http://dx.doi.org/10.1136/bmj.n71] [PMID: 33782057]

[65]
Wang-Johanning F, Frost AR, Johanning GL, et al. Expression of human endogenous retrovirus K envelope transcripts in human breast cancer. Clin Cancer Res  2001; 7(6): 1553-60.
 [PMID: 11410490]

[66]
Wang-Johanning F, Frost AR, Jian B, Epp L, Lu DW, Johanning GL. Quantitation of HERV-K env gene expression and splicing in human breast cancer. Oncogene  2003; 22(10): 1528-35.
 [http://dx.doi.org/10.1038/sj.onc.1206241] [PMID: 12629516]

[67]
Wang-Johanning F, Radvanyi L, Rycaj K, et al. Human endogenous retrovirus K triggers an antigen-specific immune response in breast cancer patients. Cancer Res  2008; 68(14): 5869-77.
 [http://dx.doi.org/10.1158/0008-5472.CAN-07-6838] [PMID: 18632641]

[68]
Wang-Johanning F, Rycaj K, Plummer JB, et al. Immunotherapeutic potential of anti-human endogenous retrovirus-K envelope protein antibodies in targeting breast tumors. J Natl Cancer Inst  2012; 104(3): 189-210.
 [http://dx.doi.org/10.1093/jnci/djr540] [PMID: 22247020]

[69]
Wang-Johanning F, Li M, Esteva FJ, et al. Human endogenous retrovirus type K antibodies and mRNA as serum biomarkers of early-stage breast cancer. Int J Cancer  2014; 134(3): 587-95.
 [http://dx.doi.org/10.1002/ijc.28389] [PMID: 23873154]

[70]
Contreras-Galindo R, Kaplan MH, Leissner P, et al. Human endogenous retrovirus K (HML-2) elements in the plasma of people with lymphoma and breast cancer. J Virol  2008; 82(19): 9329-36.
 [http://dx.doi.org/10.1128/JVI.00646-08] [PMID: 18632860]

[71]
Kaplan MH, Contreras-Galindo R, Jiagge E, et al. Is the HERV-K HML-2 Xq21.33, an endogenous retrovirus mutated by gene conversion of chromosome X in a subset of African populations, associated with human breast cancer? Infect Agent Cancer  2020; 15(1): 19.
 [http://dx.doi.org/10.1186/s13027-020-00284-w] [PMID: 32165916]

[72]
Yin H, Medstrand P, Andersson ML, Borg A, Olsson H, Blomberg J. Transcription of human endogenous retroviral sequences related to mouse mammary tumor virus in human breast and placenta: Similar pattern in most malignant and nonmalignant breast tissues. AIDS Res Hum Retroviruses  1997; 13(6): 507-16.
 [http://dx.doi.org/10.1089/aid.1997.13.507] [PMID: 9100993]

[73]
Golan M, Hizi A, Resau JH, et al. Human endogenous retrovirus (HERV-K) reverse transcriptase as a breast cancer prognostic marker. Neoplasia  2008; 10(6): 521-33.
 [http://dx.doi.org/10.1593/neo.07986] [PMID: 18516289]

[74]
Frank O, Verbeke C, Schwarz N, et al. Variable transcriptional activity of endogenous retroviruses in human breast cancer. J Virol  2008; 82(4): 1808-18.
 [http://dx.doi.org/10.1128/JVI.02115-07] [PMID: 18077721]

[75]
Zhao J, Rycaj K, Geng S, et al. Expression of human endogenous retrovirus type K envelope protein is a novel candidate prognostic marker for human breast cancer. Genes Cancer  2011; 2(9): 914-22.
 [http://dx.doi.org/10.1177/1947601911431841] [PMID: 22593804]

[76]
Rhyu DW, Kang YJ, Ock MS, et al. Expression of human endogenous retrovirus env genes in the blood of breast cancer patients. Int J Mol Sci  2014; 15(6): 9173-83.
 [http://dx.doi.org/10.3390/ijms15069173] [PMID: 24964007]

[77]
Zhou F, Krishnamurthy J, Wei Y, et al. Chimeric antigen receptor T cells targeting HERV-K inhibit breast cancer and its metastasis through downregulation of Ras. OncoImmunology  2015; 4(11): e1047582.
 [http://dx.doi.org/10.1080/2162402X.2015.1047582] [PMID: 26451325]

[78]
Zhou F, Li M, Wei Y, et al. Activation of HERV-K Env protein is essential for tumorigenesis and metastasis of breast cancer cells. Oncotarget  2016; 7(51): 84093-117.
 [http://dx.doi.org/10.18632/oncotarget.11455] [PMID: 27557521]

[79]
Lemaître C, Tsang J, Bireau C, Heidmann T, Dewannieux M. A human endogenous retrovirus-derived gene that can contribute to oncogenesis by activating the ERK pathway and inducing migration and invasion. PLoS Pathog  2017; 13(6): e1006451.
 [http://dx.doi.org/10.1371/journal.ppat.1006451] [PMID: 28651004]

[80]
Tavakolian S, Goudarzi H, Faghihloo E. Evaluating the expression level of HERV-K env, NP9, rec and gag in breast tissue. Infect Agent Cancer  2019; 14(1): 42.
 [http://dx.doi.org/10.1186/s13027-019-0260-7] [PMID: 31798679]

[81]
Chignola R, Sega M, Molesini B, Baruzzi A, Stella S, Milotti E. Collective radioresistance of T47D breast carcinoma cells is mediated by a Syncytin-1 homologous protein. PLoS One  2019; 14(1): e0206713.
 [http://dx.doi.org/10.1371/journal.pone.0206713] [PMID: 30699112]

[82]
Jin X, Xu XE, Jiang YZ, et al. The endogenous retrovirus-derived long noncoding RNA TROJAN promotes triple-negative breast cancer progression via ZMYND8 degradation. Sci Adv  2019; 5(3): eaat9820.
 [http://dx.doi.org/10.1126/sciadv.aat9820] [PMID: 30854423]

[83]
Yandım C, Karakülah G. Dysregulated expression of repetitive DNA in ER+/HER2- breast cancer. Cancer Genet  2019; 239: 36-45.
 [http://dx.doi.org/10.1016/j.cancergen.2019.09.002] [PMID: 31536958]

[84]
Ishida T, Obata Y, Ohara N, et al. Identification of the HERVK gag antigen in prostate cancer by SEREX using autologous patient serum and its immunogenicity. Cancer Immun  2008; 8: 15.
 [PMID: 19006261]

[85]
Rastogi A, Ali A, Tan SH, et al. Autoantibodies against oncogenic ERG protein in prostate cancer: Potential use in diagnosis and prognosis in a panel with C-MYC, AMACR and HERV-K Gag. Genes Cancer  2016; 7(11-12): 394-413.
 [http://dx.doi.org/10.18632/genesandcancer.126] [PMID: 28191285]

[86]
Goering W, Ribarska T, Schulz WA. Selective changes of retroelement expression in human prostate cancer. Carcinogenesis  2011; 32(10): 1484-92.
 [http://dx.doi.org/10.1093/carcin/bgr181] [PMID: 21828060]

[87]
Wang-Johanning F, Frost AR, Jian B, et al. Detecting the expression of human endogenous retrovirus E envelope transcripts in human prostate adenocarcinoma. Cancer  2003; 98(1): 187-97.
 [http://dx.doi.org/10.1002/cncr.11451] [PMID: 12833471]

[88]
Bjerregaard B, Holck S, Christensen IJ, Larsson LI. Syncytin is involved in breast cancer-endothelial cell fusions. Cell Mol Life Sci  2006; 63(16): 1906-11.
 [http://dx.doi.org/10.1007/s00018-006-6201-9] [PMID: 16871371]

[89]
Larsson LI, Holck S, Christensen IJ. Prognostic role of syncytin expression in breast cancer. Hum Pathol  2007; 38(5): 726-31.
 [http://dx.doi.org/10.1016/j.humpath.2006.10.018] [PMID: 17306327]

[90]
Reis BS, Jungbluth AA, Frosina D, et al. Prostate cancer progression correlates with increased humoral immune response to a human endogenous retrovirus GAG protein. Clin Cancer Res  2013; 19(22): 6112-25.
 [http://dx.doi.org/10.1158/1078-0432.CCR-12-3580] [PMID: 24081977]

[91]
Wallace TA, Downey RF, Seufert CJ, et al. Elevated HERV-K mRNA expression in PBMC is associated with a prostate cancer diagnosis particularly in older men and smokers. Carcinogenesis  2014; 35(9): 2074-83.
 [http://dx.doi.org/10.1093/carcin/bgu114] [PMID: 24858205]

[92]
Rezaei SD, Hayward JA, Norden S, et al. HERV-K Gag RNA and protein levels are elevated in malignant regions of the prostate in males with prostate cancer. Viruses  2021; 13(3): 449.
 [http://dx.doi.org/10.3390/v13030449] [PMID: 33802118]

[93]
Uygur B, Leikina E, Melikov K, et al. Interactions with muscle cells boost fusion, stemness, and drug resistance of prostate cancer cells. Mol Cancer Res  2019; 17(3): 806-20.
 [http://dx.doi.org/10.1158/1541-7786.MCR-18-0500] [PMID: 30587522]

[94]
Tomlins SA, Laxman B, Dhanasekaran SM, et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature  2007; 448(7153): 595-9.
 [http://dx.doi.org/10.1038/nature06024] [PMID: 17671502]

[95]
Barros-Silva JD, Paulo P, Bakken AC, et al. Novel 5′ fusion partners of ETV1 and ETV4 in prostate cancer. Neoplasia  2013; 15(7): 720-6.
 [http://dx.doi.org/10.1593/neo.13232] [PMID: 23814484]

[96]
Hermans KG, van der Korput HA, van Marion R, et al. Truncated ETV1, fused to novel tissue-specific genes, and full-length ETV1 in prostate cancer. Cancer Res  2008; 68(18): 7541-9.
 [http://dx.doi.org/10.1158/0008-5472.CAN-07-5930] [PMID: 18794142]

[97]
Li W, Lee MH, Henderson L, et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci Transl Med  2015; 7(307): 307ra153.
 [http://dx.doi.org/10.1126/scitranslmed.aac8201]

[98]
Arru G, Mameli G, Deiana GA, et al. Humoral immunity response to human endogenous retroviruses K/W differentiates between amyotrophic lateral sclerosis and other neurological diseases. Eur J Neurol  2018; 25(8): 1076-e84.
 [http://dx.doi.org/10.1111/ene.13648] [PMID: 29603839]

[99]
Garcia-Montojo M, Fathi S, Norato G, et al. Inhibition of HERV-K (HML-2) in amyotrophic lateral sclerosis patients on antiretroviral therapy. J Neurol Sci  2021; 423: 117358.
 [http://dx.doi.org/10.1016/j.jns.2021.117358] [PMID: 33653604]

[100]
Nelson P, Davari-Ejtehadi H, Nevill A, Bowman S. Endogenous retrovirus ERV-3 is not implicated in rheumatoid arthritis but may provide a biomarker for osteoarthritis. J Rheumatol  2010; 37(2): 473-3.
 [http://dx.doi.org/10.3899/jrheum.090735] [PMID: 20147487]

[101]
Garcia-Montojo M, Varade J, Villafuertes E, et al. Expression of human endogenous retrovirus HERV-K18 is associated with clinical severity in osteoarthritis patients. Scand J Rheumatol  2013; 42(6): 498-504.
 [http://dx.doi.org/10.3109/03009742.2013.779021] [PMID: 23662747]

[102]
Bendiksen S, Martinez-Zubiavrra I, Tümmler C, et al. Human endogenous retrovirus W activity in cartilage of osteoarthritis patients. BioMed Res Int  2014; 2014: 698609.
 [http://dx.doi.org/10.1155/2014/698609] [PMID: 25136615]

[103]
Dembny P, Newman AG, Singh M, et al. Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors. JCI Insight  2020; 5(7): e131093.
 [http://dx.doi.org/10.1172/jci.insight.131093] [PMID: 32271161]

[104]
Marttila S, Nevalainen T, Jylhävä J, et al. Human endogenous retrovirus HERV-K(HML-2) env expression is not associated with markers of immunosenescence. Exp Gerontol  2017; 97: 60-3.
 [http://dx.doi.org/10.1016/j.exger.2017.07.019] [PMID: 28774724]

[105]
Sankowski R, Strohl JJ, Huerta TS, et al. Endogenous retroviruses are associated with hippocampus-based memory impairment. Proc Natl Acad Sci USA  2019; 116(51): 25982-90.
 [http://dx.doi.org/10.1073/pnas.1822164116] [PMID: 31792184]

[106]
Nag N, Peterson K, Wyatt K, et al. Endogenous retroviral insertion in Cryge in the mouse No3 cataract mutant. Genomics  2007; 89(4): 512-20.
 [http://dx.doi.org/10.1016/j.ygeno.2006.12.003] [PMID: 17223009]

[107]
Chansangpetch S, Prombhul S, Tantisevi V, et al. DNA methylation status of the interspersed repetitive sequences for LINE-1, Alu, HERV-E, and HERV-K in trabeculectomy specimens from glaucoma eyes. J Ophthalmol  2018; 2018: 9171536.
 [http://dx.doi.org/10.1155/2018/9171536] [PMID: 29651348]

[108]
Sirokman G, Humphries DE, Bing OHL. Endogenous retroviral transcripts in myocytes from spontaneously hypertensive rats. Hypertension  1997; 30(1 Pt 1): 88-93.
 [http://dx.doi.org/10.1161/01.HYP.30.1.88] [PMID: 9231826]

[109]
Patience C, Simpson GR, Colletta AA, Welch HM, Weiss RA, Boyd MT. Human endogenous retrovirus expression and reverse transcriptase activity in the T47D mammary carcinoma cell line. J Virol  1996; 70(4): 2654-7.
 [http://dx.doi.org/10.1128/jvi.70.4.2654-2657.1996] [PMID: 8642702]

[110]
Ejthadi HD, Martin JH, Junying J, et al. A novel multiplex RT-PCR system detects human endogenous retrovirus-K in breast cancer. Arch Virol  2005; 150(1): 177-84.
 [http://dx.doi.org/10.1007/s00705-004-0378-8] [PMID: 15449135]

[111]
Nguyen TD, Davis J, Eugenio RA, Liu Y. Female sex hormones activate human endogenous retrovirus type K through the OCT4 transcription factor in T47D breast cancer cells. AIDS Res Hum Retroviruses  2019; 35(3): 348-56.
 [http://dx.doi.org/10.1089/aid.2018.0173] [PMID: 30565469]

[112]
Harris H, Miller OJ, Klein G, Worst P, Tachibana T. Suppression of malignancy by cell fusion. Nature  1969; 223(5204): 363-8.
 [http://dx.doi.org/10.1038/223363a0] [PMID: 5387828]

[113]
Song K, Song Y, Zhao XP, et al. Oral cancer/endothelial cell fusion experiences nuclear fusion and acquisition of enhanced survival potential. Exp Cell Res  2014; 328(1): 156-63.
 [http://dx.doi.org/10.1016/j.yexcr.2014.07.006] [PMID: 25016285]

[114]
Clawson GA, Matters GL, Xin P, et al. Macrophage-tumor cell fusions from peripheral blood of melanoma patients. PLoS One  2015; 10(8): e0134320.
 [http://dx.doi.org/10.1371/journal.pone.0134320] [PMID: 26267609]

[115]
Noubissi FK, Harkness T, Alexander CM, Ogle BM. Apoptosis-induced cancer cell fusion: A mechanism of breast cancer metastasis. FASEB J  2015; 29(9): 4036-45.
 [http://dx.doi.org/10.1096/fj.15-271098] [PMID: 26085132]

[116]
Gauck D, Keil S, Niggemann B, Zänker KS, Dittmar T. Hybrid clone cells derived from human breast epithelial cells and human breast cancer cells exhibit properties of cancer stem/initiating cells. BMC Cancer  2017; 17(1): 515.
 [http://dx.doi.org/10.1186/s12885-017-3509-9] [PMID: 28768501]

[117]
Lindström A, Midtbö K, Arnesson LG, Garvin S, Shabo I. Fusion between M2-macrophages and cancer cells results in a subpopulation of radioresistant cells with enhanced DNA-repair capacity. Oncotarget  2017; 8(31): 51370-86.
 [http://dx.doi.org/10.18632/oncotarget.17986] [PMID: 28881654]

[118]
Searles SC, Santosa EK, Bui JD. Cell-cell fusion as a mechanism of DNA exchange in cancer. Oncotarget  2017; 9(5): 6156-73.
 [http://dx.doi.org/10.18632/oncotarget.23715] [PMID: 29464062]

[119]
Lu X, Sachs F, Ramsay L, et al. The retrovirus HERVH is a long noncoding RNA required for human embryonic stem cell identity. Nat Struct Mol Biol  2014; 21(4): 423-5.
 [http://dx.doi.org/10.1038/nsmb.2799] [PMID: 24681886]

[120]
Gibb EA, Warren RL, Wilson GW, et al. Activation of an endogenous retrovirus-associated long non-coding RNA in human adenocarcinoma. Genome Med  2015; 7(1): 22.
 [http://dx.doi.org/10.1186/s13073-015-0142-6] [PMID: 25821520]
Cite As
Current Molecular Medicine

HERVs Role in the Pathogenesis, Diagnosis or Prognosis of Aging Diseases: A Systematic Review

Abstract
