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.

Microbiome in Multiple Sclerosis: Where Are We, What We Know and Do Not Know

“…However, the clinical relevance-with respect to whether these alterations contribute towards susceptibility for MS or, instead, they exert a relative protective effect-remains controversial both for adult [53,54] and pediatric populations [55,56]. In 2016, two case control studies reported distinct patterns of gut microbiota composition by the use of 16S ribosomal ribonucleic acid rRNA metagenomics analysis [57,58] (for further discussion on the potential of metagenomic techniques as applied to MS, see [59,60]). These studies provided evidence of reduced diversity in the gut microbiome of MS patients compared to controls.…”

“…MS is a complex autoimmune disease with clinical variability. As such, the establishment of a causative role for intestinal microbiota towards disease pathogenesis requires combined efforts from the field of metagenomics and other "-omics" approaches [59,60,111] with the capacity for high throughput data production and the application of these data in the context of translational medicine.…”

Human retrovirus pHEV-W envelope protein and the pathogenesis of multiple sclerosis

“…Over 30 y ago, infection with exogenous human lentiviruses was suspected (8), but differences in the presence of retroviral genome between MS and controls (9) or antibodies (10) to several retroviruses were not confirmed. It appears that, if a human retrovirus is involved, it is more likely to be through activation of retroviral genes that have been incorporated into the human genome (7,11,12). The current study by Kremer et al (13) in PNAS is important, for it does not just look at the association of pHERV-W envelope protein and MS but also examines potential mechanisms by which the protein causes axonal damage in MS. Axonal damage in white matter and loss of neurons/axons in cortical and deep gray matter are major determinants of disability in MS (14-16).…”

“…While the etiology is still unclear, the current view is that MS develops as a result of genetic predisposition and environmental triggers, with infections, smoking, childhood obesity, and deficiency of vitamin D and/or other factors related to deficient sunshine among the most likely triggers. Infections, particularly viral infections, have long been suspected as being triggers for MS and have included myxoviruses, paramyxoviruses, herpes viruses including Epstein-Barr virus (EBV), and human retroviruses (6,7). Over 30 y ago, infection with exogenous human lentiviruses was suspected (8), but differences in the presence of retroviral genome between MS and controls (9) or antibodies (10) to several retroviruses were not confirmed.…”

“…How does the possible involvement of pHEV-W square with evidence for other viruses in MS, particularly EBV? There is a role for EBV and other viruses in MS, as they can serve to activate the gene for HEV-W, leading to increased expression of the envelope protein (7,35). It is still not clear that pHEV-W is first activated within the CNS or whether activation in the CNS is initiated by infiltrating inflammatory cells which have been shown to express the envelope protein (23,36).…”