1050 journals.sagepub.com/home/msj MULTIPLE SCLEROSIS MSJ JOURNAL https://doi.org/10.1177/1352458517704711 https://doi.org/10.1177/1352458517704711 Multiple Sclerosis Journal 2017, Vol. 23(8) 1050–1055 DOI: 10.1177/ 1352458517704711 © The Author(s), 2017. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav Introduction From the early discovery and description of multiple sclerosis (MS), and particularly since John Kurtzke’s seminal epidemiological observations, 1 infections have been proposed to be involved in MS pathogene- sis. Indeed, although familial aggregation of MS cases and high MS prevalence in some ethnic populations demonstrate a genetic predisposition, latitude- dependent north-to-south gradient of disease inci- dence and migration studies point to an environmental component. Historically, the epidemiology of infec- tious triggers for MS has been described by two main hypotheses: 2 the ‘Prevalence hypothesis’ 1 and the ‘Hygiene hypothesis’. 3 The first suggests that MS is caused by a pathogen that is more prevalent in areas with high incidence of MS. This agent causes an asymptomatic persistent infection in most individu- als, and only rarely causes neurological symptoms, several years after the primary infection. The second theory postulates that early exposure to certain patho- gens is protective against immune-mediated diseases, whereas their late acquisition confers a higher risk of developing autoimmunity and allergy. 1,3 In this review, we will consider a third theory, in which an exogenous factor can induce the expression of geneti- cally transmitted endogenous retroviruses. Human endogenous retroviruses Human endogenous retroviruses (HERVs) integrated into human germ line cells 70–30 million years ago, becoming part of the human DNA and being transmit- ted through the generations. They represent up to 8% of the human genome. HERVs are classified into three classes based on their sequence identity with known exogenous retroviruses: class I, II and III, similar to gammaretroviruses, betaretroviruses, or spumavi- ruses, respectively. These classes are further divided into at least 31 families in which the letter added to HERV (HERV-W, HERV-K, HERV-H, etc.) corre- sponds to the transfer RNA (tRNA) specificity of the primer binding site. HERVs have the same genetic structure as exogenous retroviruses. Two LTR (long terminal repeat) regions delimit the genome that encodes four major viral pro- teins: Gag, the matrix and retroviral core; Pol, the reverse transcriptase; Pro, the integrase; and Env, the envelope (Figure 1). HERV expression is regulated by the promoter and enhancer regions in the LTR. In transmission over generations, endogenous retrovi- ruses generally accumulate a series of mutations and recombination events that only permit their RNA and protein expression. Accordingly, to date no human Human endogenous retroviruses and multiple sclerosis: Causation, association, or after-effect? Elena Morandi, Rachael E. Tarlinton, Radu Tanasescu and Bruno Gran Abstract: From the early days of MS discovery, infections have been proposed as a possible cause of the disease. In the last three decades, an association between human endogenous retrovirus expression and MS has been further investigated and confirmed. Nevertheless, the role of such retroviruses in the disease needs clarification. In this review, we introduce MSRV/HERV-W and describe its association with MS. We then summarize the evidence for the involvement of MSRV/HERV-W in the aetiology and progression of MS and its possible role as biomarker and drug target. Biological mechanisms for HERV effects in MS may involve the activation of innate immune pathways by the envelope protein of MSRV (MSRVEnv). In addi- tion to in vitro and experimental studies, further insight on how HERVs may influence immune-mediated pathology in MS may also come from the use of antiretroviral treatments in patients. Keywords: Multiple sclerosis, human endogenous retrovirus, MSRV, immune system Date received: 17 March 2017; accepted: 20 March 2017 Correspondence to: Bruno Gran Clinical Neurology, Division of Clinical Neuroscience, University of Nottingham School of Medicine, C Floor South Block, Queen’s Medical Centre, Nottingham NG7 2UH, UK. bruno.gran@nuh.nhs.uk Elena Morandi Clinical Neurology, Division of Clinical Neuroscience, University of Nottingham School of Medicine, Nottingham, UK Rachael E. Tarlinton School of Veterinary Medicine and Science, University of Nottingham, Nottingham, UK Radu Tanasescu Clinical Neurology, Division of Clinical Neuroscience, University of Nottingham School of Medicine, Nottingham, UK/Division of Clinical Neurosciences, Department of Neurology, University of Medicine and Pharmacy Carol Davila, Colentina Hospital, Bucharest, Romania Bruno Gran Clinical Neurology, Division of Clinical Neuroscience, University of Nottingham School of Medicine, Nottingham, UK/Department of Neurology, Nottingham University Hospitals NHS Trust, Nottingham, UK 704711MSJ 0 0 10.1177/1352458517704711Multiple Sclerosis JournalE Morandi, R Tarlinton et al. research-article 2017 Topical Review