Expert Commentary

Commentary on Jørgen Clausen’s Review – Endogenous Retroviruses in MS

J Garson University College Hospital, London [please provide full details of affiliation]

The possibility that endogenous retroviruses (ERVs) findings have not proved reproducible. In many other may be involved in multiple sclerosis (MS) and other cases the evidence remains incomplete or has yet to human autoimmune diseases has been investigated be independently confirmed. Regarding the possible intensively by several groups over the past decade, role of ERVs in MS, there has been considerable but as yet no clear consensus view has emerged and work on ERV3 and HRES-1, discussed in detail in the the topic remains controversial. The investigations in accompanying review by Jørgen Clausen (see pages man were stimulated initially by reports of ERV 22–28 of this issue). In addition, Perron and expression in a number of mouse strains that are colleagues have published on the association genetically predisposed to autoimmune disease.1 between MS and HERV-W.5 Endogenous retroviral elements in the human An extremely unusual HERV, HERV-W encodes a genome are stretches of DNA that are related to, and protein with a known function. The envelope protein possess significant sequence homology with, of this ERV is thought to mediate fusion of infectious exogenous retroviruses such as human T- cytotrophoblasts and is therefore likely to play an cell leukaemia virus (HTLV). There are a large number essential role in the formation of the human of different endogenous retroviral elements, often placenta.2 HERV-W was originally discovered during present in multiple copies, and altogether they are studies of retroviral particles associated with MS, and estimated to constitute as much as 8% of the human was initially designated MS-associated retrovirus, genome.2 The vast majority of these elements are MSRV.6 The detection of virion-associated MSRV RNA defective, however, due to the presence of in the serum of patients with MS7 has been accumulated mutations including deletions and stop independently confirmed in Sardinia, an island with codons, and are therefore unable to encode viable an unusually high incidence of the disease.8 Further infectious retroviral particles. Nevertheless, a small investigations in Sardinian patients have revealed subset does possess intact open reading frames; that MSRV expression may also be associated with therefore, these elements have the potential to other inflammatory neurological diseases9 and that, encode, and even express, certain functional in MS, the detection of MSRV RNA in cerebrospinal retroviral-like proteins. The origin of endogenous fluid may be a prognostic factor correlated with retroviral sequences is uncertain, but it is generally disability progression.10 HERV-W has also recently thought that they represent the remnants of ancestral been implicated in the development of schizophrenia retroviral infections that have become fixed within but this finding has yet to be reproduced by other germline DNA and are therefore inherited in a groups.11 Mendelian fashion. If future studies confirm the association between Several human endogenous retroviruses (HERVs) MS and HERV-W, ERV-3, HRES-1 or any other have been claimed as potential aetiological agents HERV,12 the question of potential pathogenic for a variety of malignancies, autoimmune diseases mechanisms will become central. In the case of and neurological disorders.3 In some cases, such as HERV-W, it has been demonstrated that the envelope the proposed involvement of a human endogenous protein acts as a superantigen* (referred to as an retroviral superantigen in type 1 diabetes,4 the autoantigen in Clausen’s paper**). Researchers have

20 The International MS Journal 2003; 10: 20–21 Expert Commentary

proposed that this could trigger or contribute to the and placental expression of 11. Karlsson H, Bachmann S, HERV-W, a new human Schroder J, McArthur J, Torrey 13 autoimmune dysregulation seen in MS. Evidence endogenous retrovirus family. J EF, Yolken RH. Retroviral RNA Virol 1999; 73: 1175–1185. identified in the cerebrospinal suggesting that HERV-W might be associated with a 6. Perron H, Garson JA, Bedin F, fluids and brains of individuals novel gliotoxin has also been presented;14 however, Beseme F, Paranhos-Baccala G, with schizophrenia. Proc Natl Komurian-Pradel F et al. The Acad Sci U S A 2001; 98: it is important to recognize that for HERVs generally, Collaborative Research Group 4634–4639. on MS. Molecular identification 12. Christensen T, Dissing-Sorensen these potential pathogenic mechanisms are currently of a novel retrovirus repeatedly P, Riemann H, Hansen HJ, in the realm of speculation. It remains possible that isolated from patients with Moller-Larsen A. Expression of multiple sclerosis. Proc Natl sequence variants of HERV expression simply represents an Acad Sci U S A 1997; 94: endogenous retrovirus RGH in 7583–7588. particle form in multiple epiphenomenon and that the associations may prove 7. Garson JA, Tuke PW, Giraud P, sclerosis. Lancet 1998; 352: to be casual rather than causal. Although research in Paranhos-Baccaia G, Perron P. 1033. Detection of virion-associated 13. Perron H, Jouvin-Marche E, this area has revealed many intriguing findings, MSRV-RNA in serum of patients Michel M, Ounanian-Paraz A, with multiple sclerosis. Lancet Camelo S, Dumon A et al. much more work is needed before any truly coherent 1998; 351: 33. Multiple sclerosis retrovirus picture can be expected to emerge. 8. Serra C, Sotgiu S, Mameli G, particles and recombinant Pugliatti M, Rosati G, Dolei A. envelope trigger an abnormal Multiple sclerosis and multiple immune response in vitro, by sclerosis-associated retrovirus in inducing polyclonal V? 16 T- References Sardinia. Neurol Sci 2001; 22: lymphocyte activation. Virology 171–173. 2001; 287: 321–332. 1. Boeke JD, Stoye JP. 3. Lower R. The pathogenic 9. Dolei A, Serra C, Mameli G, 14. Menard A, Paranhos-Baccala Retrotransposons, endogenous potential of endogenous Pugliatti M, Sechi G, Cirotto G, Pelletier J, Mandrand B, retroviruses, and the evolution retroviruses: facts and fantasies. MC et al. Multiple sclerosis- Seigneurin JM, Perron H, Reiger of retroelements. In: Retroviruses Trends Microbiol 1999: 7: associated retrovirus (MSRV) in F. A cytotoxic factor for glial (Coffin JM, Hughes SH, Varmus 350–356. Sardinian MS patients. cells: a new avenue of research HE, eds). Cold Spring Harbor 4. Conrad B, Weissmahr RN, Boni Neurology 2002; 58: for multiple sclerosis? Cell Mol Laboratory Press, 1997; page J Arcari R, Schupbach J, Mach 471–473.1 Biol (Noisy-le-grand) 1997; 43: range? B. A human endogenous 10. Sotgiu S, Serra C, Mameli G, 889–901. 2. Griffiths DJ. Endogenous retroviral superantigen as Pugliatti M, Rosati G, Arru G, retroviruses in the human candidate autoimmune gene in Dolei A. Multiple sclerosis- genome sequence. Genome type 1 diabetes. Cell 1997; 90: associated retrovirus and MS Biology 2001; 2: 303–313. prognosis: an observational 1017.1–1017.5. 5. Blond JL, Beseme F, Duret L, study. Neurology 2002; 9: http://genomebiology.com/20 Bouton O, Bedin F, Perron H et 1071–1073 01/2/6/reviews/1017 al. Molecular characterization

*Antigens occurring in bacterial or viruses which are able to activate T cells non-specifically (according to Dorland’s Medical Dictionary, WB Saunders Company). **A normal tissue constituent which is the target of an immune response (according to Dorland’s Medical Dictionary, WB Saunders Company). Please check that you are happy with these definitions.

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