Viruses and endogenous retroviruses in multiple sclerosis: From correlation to causation

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The prevalence of multiple sclerosis (MS) has steadily increased over the last five decades. This high socio‐economic burden, together with its challenging management especially when chronic and progressive, underscores the need for further research to determine its exact aetiology. MS is a multifactorial disease that arises from a complex interaction between genetic (notably immunogenetic), autoimmune and environmental factors.1 Environmental‐immune system interactions are increasingly recognized as important in MS pathophysiology6 and are likely to explain the discordant MS incidence in monozygotic twins that cannot be attributed to genomic, transcriptomic or epigenomic factors alone.8 Furthermore, the environment represents a modifiable factor in contrast to the genomic landscape, so it is of particular interest from the perspective of prevention.
MS was initially proposed to be of infectious origin at the end of the 19th century, but the development of the experimental allergic encephalitis (EAE) model in 1934 shifted attention away from microorganisms and towards an allergy‐related and then autoimmune basis for the disease. However, a myelin‐targeting autoimmune model does not fully explain the segmental distribution of lesions as myelin is ubiquitous in the central nervous system (CNS),9 and auto‐antigens are neither pathognomonic nor universal in MS.10 In addition, some authors have suggested that the EAE model might more closely represent immunologically induced encephalomyelitis rather than demyelination.11
However, the microbial aetiological theory—in which viruses take centre stage—has not been abandoned but has flourished in the light of mainly indirect discoveries of different viruses in MS.13 Although direct evidence for causative viruses in MS has generally been lacking, accumulated evidence from human and animal studies supports a role for viruses as at least a trigger for MS.2 Epidemiological evidence in support of this theory includes observations of MS epidemics in the Faroe Islands in the 1980s, and more recently, MS clusters in Ottawa, Canada.14
Although the evidence for a causative viral aetiology for MS in humans remains inconclusive, viruses appear to play a role in modulating the neuro‐immunological system of genetically susceptible individuals to cause MS. For instance, IgG antibodies against several viruses including varicella zoster virus (VZV), cytomegalovirus (CMV), measles, rubella, mumps and herpes simplex virus (HSV‐1) have been identified in the cerebrospinal fluid (CSF) of patients with MS.15 More recently, other viruses have attracted attention including Saffold virus (a novel human cardiovirus).17 With this in mind, this review provides an in‐depth discussion of the viruses implicated in MS pathogenesis. We first consider viruses with the greatest evidence base, namely Epstein‐Barr virus (EBV), human herpesvirus (HHV‐6), VZV, human endogenous retroviruses (HERV) and then go on to describe the potential roles for “minor” viruses in MS. We focus on the connection between viruses and MS pathophysiology rather than its clinical progression, and we highlight the limitations of existing studies and possible future research directions.

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