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

Abstract

Multiple sclerosis is an immune-mediated disease with an environmental component. According to a long-standing but unproven hypothesis dating to initial descriptions of multiple sclerosis (MS) at the end of the 19th century, viruses are either directly or indirectly implicated in MS pathogenesis. Whether viruses in MS are principally causal or simply contributory remains to be proven, but many viruses or viral elements-predominantly Epstein-Barr virus, human endogenous retroviruses (HERVs) and human herpesvirus 6 (HHV-6) but also less common viruses such as Saffold and measles viruses-are associated with MS. Here, we present an up-to-date and comprehensive review of the main candidate viruses implicated in MS pathogenesis and summarize how these viruses might cause or lead to the hallmark demyelinating and inflammatory lesions of MS. We review data from epidemiological, animal and in vitro studies and in doing so offer a transdisciplinary approach to the topic. We argue that it is crucially important not to interpret "absence of evidence" as "evidence of absence" and that future studies need to focus on distinguishing correlative from causative associations. Progress in the MS-virus field is expected to arise from an increasing body of knowledge on the interplay between viruses and HERVs in MS. Such interactions suggest common HERV-mediated pathways downstream of viral infection that cause both neuroinflammation and neurodegeneration. We also comment on the limitations of existing studies and provide future research directions for the field.

Keywords: Epstein-Barr virus; human endogenous retroviruses; human herpesvirus 6; multiple sclerosis; viruses.

Figure 1

Putative mechanisms of human endogenous retrovirus (HERV)‐related autoimmunity in multiple sclerosis. (A) HERV‐encoded RNAs with intact open reading frames (ORFs) can be translated into proteins. Some of these (eg HERV‐K, HCML‐ARV) are in close proximity to SNPs shown to be associated with MS in genomewide association studies and representing genes involved in immune responses and vitamin D metabolism. (B) Some HERV proteins, notably MASP‐3, HERV‐H and HERV‐W, are expressed on the surface of normal cells including B cells. This serological response may be associated with autoimmunity, although causality has yet to be established. (C) HERVs are integral to the human genome but are epigenetically inactivated under normal conditions. HERV expression may be induced by environmental triggers including HSV‐1, HHV‐6, VZV and EBV viruses to stimulate an immune response and autoimmunity. (D) The MRSV‐Env protein has been identified in MS plaques and is brain selective and immunopathogenic so may directly stimulate an autoimmune response.1 Furthermore, this protein inhibits differentiation of oligodendrocyte precursors so may have a negative feedback effect in the brains of patients with MS 2