Mammalian genomes contain a heavy load (42% in humans) of retroelements, which are mobile sequences requiring reverse transcription for their replicative transposition. A significant proportion of these elements is of retroviral origin, with thousands of sequences resembling the integrated form of infectious retroviruses, with two LTRs bordering internal regions homologous to the gag, prt, pol, and env genes. These elements, named endogenous retroviruses (ERVs), are most probably the proviral remnants of ancestral germ-line infections by active retroviruses, which have thereafter been transmitted in a Mendelian manner. The complete sequencing of the human genome now allows a comprehensive survey of human ERVs (HERVs), which can be grouped according to sequence homologies into approximately 80 distinct families, each containing a few to several hundred elements. As reviewed here, strong similarities between HERVs and present-day retroviruses can be inferred from phylogenetic analyses on the reverse transcriptase (RT) domain of the pol gene or the transmembrane subunit (TM) of the env gene, which disclose interspersion of both classes of elements and suggest a common history and shared ancestors. Similarities are also observed at the functional levels, since despite the fact that most HERVs have accumulated mutations, deletions, and/or truncations, several elements still possess some of the functions of retroviruses, with evidence for viral-like particle formation, and occurrence of envelope proteins allowing cell-cell fusion and even conferring infectivity to pseudotypes. Along this line, a genomewide screening for human retroviral genes with coding capacity has revealed 16 fully coding envelope genes. These genes are transcribed in several healthy tissues including the placenta, three of them at a very high level. Besides their impact in modelling the genome, HERVs thus appear to contain still active genes, which most probably have been subverted by the host for its benefit and should be considered as bona fide human genes. Some of their characteristic features and possible physiological roles, as well as potential pathological effects inherited from their retroviral ancestors are also reviewed.   

Acha-Orbea H, MacDonald HR: Superantigens of mouse mammary tumor virus. Annu Rev Immunol 13:459–486 (1995).
An DS, Xie Y-M, Chen ISY: Envelope gene of the human endogenous retrovirus HERV-W encodes a functional retrovirus envelope. J Virol 75:3488–3489 (2001).
Andersson ML, Lindeskog M, Medstrand P, Westley B, May F, Blomberg J: Diversity of human endogenous retrovirus class II-like sequences. J Gen Virol 80:255–260 (1999).
Barbulescu M, Turner G, Seaman MI, Deinard AS, Kidd KK, Lenz J: Many human endogenous retrovirus K (HERV-K) proviruses are unique to humans. Curr Biol 9:861–868 (1999).
Benit L, de Parseval N, Casella J-F, Callebaud I, Cordonnier A, Heidmann T: Cloning of a new murine endogenous retrovirus, MERV-L, with strong homology to the human HERV-L element and with a gag coding sequence closely related to the Fv-1 restriction gene. J Virol 71:5652–5657 (1997).
Benit L, Lallemand J-B, Casella J-F, Philippe H, Heidmann T: ERV-L elements: a family of endogenous retrovirus-like elements active throughout the evolution of mammals. J Virol 73:3301–3308 (1999).
Benit L, Dessen P, Heidmann T: Identification, phylogeny, and evolution of retroviral elements based on their envelope genes. J Virol 75:11709–11719 (2001).
Benit L, Calteau A, Heidmann T: Characterization of the low-copy HERV-Fc family: evidence for recent integrations in primates of elements with coding envelope genes. Virology 312:159–168 (2003).
Bernstein E, Denli AM, Hannon GJ: The rest is silence. RNA 7:1509–1521 (2001).
Best S, Le Tissier PR, Stoye JP: Endogenous retroviruses and the evolution of resistance to retroviral infection. Trends Microbiol 5:313–318 (1997).
Bieda K, Hoffmann A, Boller K: Phenotypic heterogeneity of human endogenous retrovirus particles produced by teratocarcinoma cell lines. J Gen Virol 82:591–596 (2001).
Blaise S, Mangeney M, Heidmann T: The envelope of Mason-Pfizer monkey virus has immunosuppressive properties. J Gen Virol 82:1597–1600 (2001).
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 100:13013–13018 (2003).
Blaise S, Ruggieri A, Dewannieux M, Cosset F-L, Heidmann T: Identification of an envelope protein from the FRD family of Human Endogenous Retroviruses (HERV-FRD) conferring infectivity on retroviral particles and functional conservation among simians. J Virol 78:1050–1054 (2004).
Blond J-L, Besème F, Duret L, Bouton O, Bedin F, Perron H, Mandrand B, Mallet F: Molecular characterization and placental expression of HERV-W, a new human endogenous retrovirus family. J Virol 73:1175–1185 (1999).
Blond JL, Lavillette D, Cheynet V, Bouton O, Oriol G, Chapel-Fernandes S, Mandrand B, Mallet F, Cosset F-L: 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 74:3321–3329 (2000).
Boeke JD, Stoye JP: Retrotransposons, endogenous retroviruses, and the evolution of retroelements, in Coffin JM, Hughes SH, Varmus HE (eds): Retroviruses, pp 343–436 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1997).
Boese A, Sauter M, Galli U, Best B, Herbst H, Mayer J, Kremmer E, Roemer K, Mueller-Lantzsch N: Human endogenous retrovirus protein cORF supports cell transformation and associates with the promyelocytic leukemia zinc finger protein. Oncogene 19:4328–4336 (2000).
Boller K, König H, Sauter M, Mueller-Lantzsch N, Löwer R, Löwer J, Kurth R: Evidence that HERV-K is the endogenous retrovirus sequence that codes for the human teratocarcinoma-derived retrovirus HTDV. Virology 196:349–353 (1993).
Bucheton A, Vaury C, Chaboissier M-C, Abad P, Pélisson A, Simonelig M: I elements and the Drosophila genome, in McDonald JF (ed): Transposable Elements and Evolution, pp 173–188 (Kluwer Academic Publishers, Amsterdam 1993).
Cianciolo GJ, Copeland T, Orozlan S, Snyderman R: Inhibition of lymphocyte proliferation by a synthetic peptide homologous to retroviral envelope protein. Science 230:453–455 (1985).
Cohen M, Powers M, O’Connell C, Kato N: The nucleotide sequence of the env gene from the human provirus erv3 and isolation and characterization of an erv3-specific cDNA. Virology 147:449–458 (1985).
Cowan S, Hatziioannou T, Cunningham T, Muesing MA, Gottlinger HG, Bieniasz PD: Cellular inhibitors with Fv1-like activity restrict human and simian immunodeficiency virus tropism. Proc Natl Acad Sci USA 99:11914–11919 (2002).
de Parseval N, Heidmann T: Physiological knock-out of the envelope gene of the single copy ERV-3 human endogenous retrovirus in a fraction of the caucasian population. J Virol 72:3442–3445 (1998).
de Parseval N, Casella JF, Gressin L, Heidmann T: Characterization of the three HERV-H proviruses with an open envelope reading frame encompassing the immunosuppressive domain and evolutionary history in primates. Virology 279:558–569 (2001).
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 77:10414–10422 (2003).
Deininger PL, Batzer MA: Mammalian retroelements. Genome Res 12:1455–65 (2002).
Doolittle RF, Feng DF, Johnson MS, McClure MA: Origins and evolutionary relationships of retroviruses. Quart Rev Biology 64:1–30 (1989).
Dunn CA, Medstrand P, Mager DL: An endogenous retroviral long terminal repeat is the dominant promoter for human beta1,3-galactosyltransferase 5 in the colon. Proc Natl Acad Sci USA 8:12841–12846 (2003).
Dupressoir A, Heidmann T: Germ line-specific expression of intracisternal A-particule retrotransposons in transgenic mice. Mol Cell Biol 16:4495–4503 (1996).
Engels WR: P Elements in Drosophila melanogaster, in Berg D, Howe M (eds): Mobile DNA, pp 437–484 (American Society for Microbiology, Washington, D.C. 1989).
Ericsson TA, Takeuchi Y, Templin C, Quinn G, Farhadian SF, Wood JC, Oldmixon BA, Suling KM, Ishii JK, Kitagawa Y, Miyazawa T, Salomon DR, Weiss RA, Patience C: Identification of receptors for pig endogenous retrovirus. Proc Natl Acad Sci USA 9:6759–6764 (2003).
Firouzi R, Rolland A, Michel M, Jouvin-Marche E, Hauw JJ, Malcus-Vocanson C, Lazarini F, Gebuhrer L, Seigneurin JM, Touraine JL, Sanhadji K, Marche PN, Perron H: Multiple sclerosis-associated retrovirus particles cause T lymphocyte-dependent death with brain hemorrhage in humanized SCID mice model. J Neurovirol 9:79–93 (2003).
Frendo JL, Olivier D, Cheynet V, Blond JL, Bouton O, Vidaud M, Rabreau M, Evain-Brion D, Mallet F: Direct involvement of HERV-W Env glycoprotein in human trophoblast cell fusion and differentiation. Mol Cell Biol 23:3566–3574 (2003).
Hatziioannou T, Cowan S, Goff SP, Bieniasz PD, Towers GJ: Restriction of multiple divergent retroviruses by Lv1 and Ref1. EMBO J 22:385–394 (2003).
Herniou E, Martin J, Miller K, Cook J, Wilkinson M, Tristem M: Retroviral diversity and distribution in vertebrates. J Virol 72:5955–5966 (1998).
Herve CA, Forrest G, Lower R, Griffiths DJ, Venables PJ: Conservation and loss of the ERV3 open reading frame in primates. Genomics 83:940–943 (2004).
International Human Genome Sequencing Consortium: Initial sequencing and analysis of the human genome. Nature 409:860–921 (2001).
Jensen S, Gassama M-P, Heidmann T: Taming of transposable elements by homology-dependent gene silencing. Nat Genet 21:209–212 (1999).
Johnson WE, Coffin JM: Constructing primate phylogenies from ancient retrovirus sequences. Proc Natl Acad Sci USA 96:10254–10260 (1999).
Jurka J: Repbase update, a database an an electronic journal of repetitive elements. Trends Genet 16:418–420 (2000).
Kowalski PE, Mager DL: A human endogenous retrovirus suppresses translation of an associated fusion transcript, PLA2L. J Virol 72:6164–6168 (1998).
Lindeskog M, Mager D, Blomberg J: Isolation of a human endogenous retroviral HERV-H element with an open env reading frame. Virology 258:441–450 (1999).
Löwer R: The pathogenic potential of endogenous retroviruses: facts and fantasies. Trends Microbiol 7:350–356 (1999).
Löwer R, Boller K, Hasenmeier B, Korbmacher C, Mueller-Lantzsch N, Löwer J, Kurth R: Identification of human endogenous retrovirus with complex mRNA expression and particle formation. Proc Natl Acad Sci USA 90:4480–4484 (1993).
Löwer R, Löwer J, Kurth R: The viruses in all of us: characteristics and biological significance of human endogenous retrovirus sequences. Proc Natl Acad Sci USA 93:5177–5184 (1996).
Lynch C, Tristem M: A co-opted gypsy-type LTR-retrotransposon is conserved in the genomes of humans, sheep, mice, and rats. Curr Biol 13:1518–1523 (2003).
Maeda N, Palmarini M, Murgia C, Fan H: Direct transformation of rodent fibroblasts by jaagsiekte sheep retrovirus DNA. Proc Natl Acad Sci USA 98:4449–4454 (2001).
Malik HS, Eickbush TH: Phylogenetic analysis of ribonuclease H domains suggests a late, chimeric origin of LTR retrotransposable elements and retroviruses. Genome Res 11:1187–1197 (2001).
Malik HS, Henikoff S, Eickbush TH: Poised for contagion: evolutionary origins of the infectious abilities of invertebrate retroviruses. Genome Res 10:1307–1318 (2000).
Mallet F, Bouton O, Prudhomme S, Cheynet V, Oriol G, Bonnaud B, Lucotte G, Duret L, Mandrand B: The endogenous retroviral locus ERVWE1 is a bona fide gene involved in hominoid placental physiology. Proc Natl Acad Sci USA 101:1731–1736 (2004).
Mangeney M, Heidmann T: Tumor cells expressing a retroviral envelope escape immune rejection in vivo. Proc Natl Acad Sci USA 95:14920–14925 (1998).
Mangeney M, de Parseval N, Thomas G, Heidmann T: The full-length envelope of an HERV-H human endogenous retrovirus has immunosuppressive properties. J Gen Virol 82:2515–2518 (2001).
Martin J, Herniou E, Cook J, Waugh O’Neill R, Tristem M: Human endogenous type-I-related viruses have an apparently widespread distribution within vertebrates. J Virol 71:437–443 (1997).
Mayer J, Sauter M, Racz A, Scherer D, Mueller-Lantzsch N, Meese E: An almost-intact human endogenous retrovirus K on human chromosome 7. Nat Genet 21:257–258 (1999).
Nakagawa K, Harrison LC: The potential roles of endogenous retroviruses in autoimmunity. Immun Rev 152:193–236 (1996).
Ostertag EM, Kazazian HH Jr: Biology of mammalian L1 retrotransposons. Annu Rev Genet 35:501–538 (2001).
Pinter A, Kopelman R, Li Z, Kayman SC, Sanders DA: Localization of the labile disulfide bond between SU and TM of the murine leukemia virus envelope protein complex to a highly conserved CWLC motif in SU that resembles the active-site sequence of thiol-disulfide exchange enzymes. J Virol 71:8073–8077 (1997).
Rai SK, Duh FM, Vigdorovich V, Danilkovitch-Miagkova A, Lerman MI, Miller AD: Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation. Proc Natl Acad Sci USA 98:4443–4448 (2001).
Reus K, Mayer J, Sauter M, Zischler H, Muller-Lantzsch N, Meese E: HERV-K (OLD): ancestor sequences of the human endogenous retrovirus family HERV-K (HML-2). J Virol 75:8917–8926 (2001).
Rosenberg N, Jolicoeur P: Retroviral pathogenesis, in Coffin JM, Hughes, CL, Varmus, HE (eds): Retroviruses, pp 475–586 (Cold Spring Harbor Laboratory Press, New York 1997).
Schulte AM, Lai S, Kurtz A, Czubayko F, Riegel AT: Human trophoblast and choriocarcinoma expression of the growth factor pleiotrophin attributable to germ-line insertion of an endogenous retrovirus. Proc Natl Acad Sci USA 93:14759–14764 (1996).
Shih A, Coutavas E, Rush MG: Evolutionary implications of primate endogenous retroviruses. Virology 182:495–502 (1991).
Stauffer Y, Marguerat S, Meylan F, Ucla C, Sutkowski N, Huber B, Pelet T, Conrad B: Interferon-alpha-induced endogenous superantigen. A model linking environment and autoimmunity. Immunity 15:591–601 (2001).
Stoye JP: Endogenous retroviruses: still active after all these years? Curr Biol 11:914–916 (2001).
Sutkowski N, Conrad B, Thorley-Lawson DA, Huber BT: Epstein-Barr virus transactivates the human endogenous retrovirus HERV-K18 that encodes a superantigen. Immunity 15:579–589 (2001).
Tchenio T, Heidmann T: Defective retrovirus can disperse in the human genome by intracellular transposition. J Virol 65:2113–2118 (1991).
Ting C-N, Rosenberg MP, Snow CM, Samuelson LC, Meisler MH: Endogenous retroviral sequences are required for tissue-specific expression of a human salivary amylase gene. Genes Dev 6:1457–1465 (1992).
Tönjes RR, Czauderna F, Kurth R: Genome-wide screening, cloning, chromosomal assignment, and expression of full-length human endogenous retrovirus type K. J Virol 73:9187–9195 (1999).
Towers G, Bock M, Martin S, Takeuchi Y, Stoye JP, Danos O: A conserved mechanism of retrovirus restriction in mammals. Proc Natl Acad Sci USA 97:12295–12299 (2000).
Tristem M: Identification and characterization of novel human endogenous retrovirus families by phylogenetic screening of the human genome mapping project database. J Virol 74:3715–3730 (2000).
Turner G, Barbulescu M, Su M, Jensen-Seaman MI, Kidd KK, Lenz J: Insertional polymorphisms of full-length endogenous retroviruses in humans. Curr Biol 11:1531–1535 (2001).
van de Lagemaat LN, Landry JR, Mager DL, Medstrand P: Transposable elements in mammals promote regulatory variation and diversification of genes with specialized functions. Trends Genet 19:530–536 (2003).
Venables S, Brookes M, Fan W, Larsson E, Maini RN, Boyd MT: Abundance of an endogenous retroviral envelope protein in placental trophoblast suggests a biological function. Virology 211:589–592 (1995).
Xiong Y, Eickbush TH: Origin and evolution of retroelements based upon their reverse transcriptase sequence. EMBO J 9:3353–3362 (1990).
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.