Garson, JA

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UCL Discovery

20 The International MS Journal 2003; 10: 20–21Expert CommentaryThe possibility that endogenous retroviruses (ERVs)may be involved in multiple sclerosis (MS) and otherhuman autoimmune diseases has been investigatedintensively by several groups over the past decade,but as yet no clear consensus view has emerged andthe topic remains controversial. The investigations inman were stimulated initially by reports of ERVexpression in a number of mouse strains that aregenetically predisposed to autoimmune disease.1Endogenous retroviral elements in the humangenome are stretches of DNA that are related to, andpossess significant sequence homology with,infectious exogenous retroviruses such as human T-cell leukaemia virus (HTLV). There are a large numberof different endogenous retroviral elements, oftenpresent in multiple copies, and altogether they areestimated to constitute as much as 8% of the humangenome.2 The vast majority of these elements aredefective, however, due to the presence ofaccumulated mutations including deletions and stopcodons, and are therefore unable to encode viableinfectious retroviral particles. Nevertheless, a smallsubset does possess intact open reading frames;therefore, these elements have the potential toencode, and even express, certain functionalretroviral-like proteins. The origin of endogenousretroviral sequences is uncertain, but it is generallythought that they represent the remnants of ancestralretroviral infections that have become fixed withingermline DNA and are therefore inherited in aMendelian fashion.Several human endogenous retroviruses (HERVs)have been claimed as potential aetiological agentsfor a variety of malignancies, autoimmune diseasesand neurological disorders.3 In some cases, such asthe proposed involvement of a human endogenousretroviral superantigen in type 1 diabetes,4 thefindings have not proved reproducible. In many othercases the evidence remains incomplete or has yet tobe independently confirmed. Regarding the possiblerole of ERVs in MS, there has been considerablework on ERV3 and HRES-1, discussed in detail in theaccompanying review by Jørgen Clausen (see pages22–28 of this issue). In addition, Perron andcolleagues have published on the associationbetween MS and HERV-W.5An extremely unusual HERV, HERV-W encodes aprotein with a known function. The envelope proteinof this ERV is thought to mediate fusion ofcytotrophoblasts and is therefore likely to play anessential role in the formation of the humanplacenta.2 HERV-W was originally discovered duringstudies of retroviral particles associated with MS, andwas initially designated MS-associated retrovirus,MSRV.6 The detection of virion-associated MSRV RNAin the serum of patients with MS7 has beenindependently confirmed in Sardinia, an island withan unusually high incidence of the disease.8 Furtherinvestigations in Sardinian patients have revealedthat MSRV expression may also be associated withother inflammatory neurological diseases9 and that,in MS, the detection of MSRV RNA in cerebrospinalfluid may be a prognostic factor correlated withdisability progression.10 HERV-W has also recentlybeen implicated in the development of schizophreniabut this finding has yet to be reproduced by othergroups.11If future studies confirm the association betweenMS and HERV-W, ERV-3, HRES-1 or any otherHERV,12 the question of potential pathogenicmechanisms will become central. In the case ofHERV-W, it has been demonstrated that the envelopeprotein acts as a superantigen* (referred to as anautoantigen in Clausen’s paper**). Researchers haveCommentary on Jørgen Clausen’sReview – Endogenous Retrovirusesin MSJ GarsonUniversity College Hospital, London [please provide full details of affiliation]The International MS Journal 2003; 10: 20–21 21Expert Commentaryproposed that this could trigger or contribute to theautoimmune dysregulation seen in MS.13 Evidencesuggesting that HERV-W might be associated with anovel gliotoxin has also been presented;14 however,it is important to recognize that for HERVs generally,these potential pathogenic mechanisms are currentlyin the realm of speculation. It remains possible thatHERV expression simply represents anepiphenomenon and that the associations may proveto be casual rather than causal. Although research inthis area has revealed many intriguing findings,much more work is needed before any truly coherentpicture can be expected to emerge.References*Antigens occurring in bacterial or viruses which are able toactivate T cells non-specifically (according to Dorland’s MedicalDictionary, WB Saunders Company).**A normal tissue constituent which is the target of an immuneresponse (according to Dorland’s Medical Dictionary, WBSaunders Company). Please check that you are happywith these definitions.1. Boeke JD, Stoye JP.Retrotransposons, endogenousretroviruses, and the evolutionof retroelements. In: Retroviruses(Coffin JM, Hughes SH, VarmusHE, eds). Cold Spring HarborLaboratory Press, 1997; pagerange?2. Griffiths DJ. Endogenousretroviruses in the humangenome sequence. GenomeBiology 2001; 2:1017.1–1017.5.http://genomebiology.com/2001/2/6/reviews/10173. Lower R. The pathogenicpotential of endogenousretroviruses: facts and fantasies.Trends Microbiol 1999: 7:350–356.4. Conrad B, Weissmahr RN, BoniJ Arcari R, Schupbach J, MachB. A human endogenousretroviral superantigen ascandidate autoimmune gene intype 1 diabetes. Cell 1997; 90:303–313.5. Blond JL, Beseme F, Duret L,Bouton O, Bedin F, Perron H etal. Molecular characterizationand placental expression ofHERV-W, a new humanendogenous retrovirus family. JVirol 1999; 73: 1175–1185.6. Perron H, Garson JA, Bedin F,Beseme F, Paranhos-Baccala G,Komurian-Pradel F et al. TheCollaborative Research Groupon MS. Molecular identificationof a novel retrovirus repeatedlyisolated from patients withmultiple sclerosis. Proc NatlAcad Sci U S A 1997; 94:7583–7588.7. Garson JA, Tuke PW, Giraud P,Paranhos-Baccaia G, Perron P.Detection of virion-associatedMSRV-RNA in serum of patientswith multiple sclerosis. Lancet1998; 351: 33.8. Serra C, Sotgiu S, Mameli G,Pugliatti M, Rosati G, Dolei A.Multiple sclerosis and multiplesclerosis-associated retrovirus inSardinia. Neurol Sci 2001; 22:171–173.9. Dolei A, Serra C, Mameli G,Pugliatti M, Sechi G, CirottoMC et al. Multiple sclerosis-associated retrovirus (MSRV) inSardinian MS patients.Neurology 2002; 58:471–473.110. Sotgiu S, Serra C, Mameli G,Pugliatti M, Rosati G, Arru G,Dolei A. Multiple sclerosis-associated retrovirus and MSprognosis: an observationalstudy. Neurology 2002; 9:1071–107311. Karlsson H, Bachmann S,Schroder J, McArthur J, TorreyEF, Yolken RH. Retroviral RNAidentified in the cerebrospinalfluids and brains of individualswith schizophrenia. Proc NatlAcad Sci U S A 2001; 98:4634–4639.12. Christensen T, Dissing-SorensenP, Riemann H, Hansen HJ,Moller-Larsen A. Expression ofsequence variants ofendogenous retrovirus RGH inparticle form in multiplesclerosis. Lancet 1998; 352:1033.13. Perron H, Jouvin-Marche E,Michel M, Ounanian-Paraz A,Camelo S, Dumon A et al.Multiple sclerosis retrovirusparticles and recombinantenvelope trigger an abnormalimmune response in vitro, byinducing polyclonal V? 16 T-lymphocyte activation. Virology2001; 287: 321–332.14. Menard A, Paranhos-BaccalaG, Pelletier J, Mandrand B,Seigneurin JM, Perron H, ReigerF. A cytotoxic factor for glialcells: a new avenue of researchfor multiple sclerosis? Cell MolBiol (Noisy-le-grand) 1997; 43:889–901.

A cytotoxic factor for glial cells: a new avenue of research for multiple sclerosis? Cell Mol Biol (Noisy-le-grand)

A human endogenous retroviral superantigen as candidate autoimmune gene in type 1 diabetes. Cell

Detection of virion-associated MSRV-RNA in serum of patients with multiple sclerosis. Lancet

Dumon A et al. Multiple sclerosis retrovirus particles and recombinant envelope trigger an abnormal immune response in vitro, by inducing polyclonal V? 16 Tlymphocyte activation. Virology

endogenous retroviruses, and the evolution of retroelements. In: Retroviruses

Expression of sequence variants of endogenous retrovirus RGH in particle form in multiple sclerosis. Lancet

Molecular characterization and placental expression of HERV-W, a new human endogenous retrovirus family.

Multiple sclerosis and multiple sclerosis-associated retrovirus in Sardinia. Neurol Sci

Multiple sclerosisassociated retrovirus (MSRV) in Sardinian MS patients. Neurology 2002; 58: 471–473.1 10. Sotgiu

The Collaborative Research Group on MS. Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis.

Endogenous retrovirusesin MS

Endogenous retrovirusesin MS

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