Review ArticleAssociation between human herpesvirus & human endogenous retrovirus and MS onset & progression
Introduction
Multiple sclerosis (MS) is a chronic and progressive inflammatory disease, causing demyelination, axonal loss and atrophy of the central nervous system. The aetiology of MS is due to interplay between genetic and environmental/behavioural factors [1], [2]. For genetic factors, associations between the HLA-DR locus and MS have been consistently demonstrated, with the strongest of these being HLA-DRB1*1501 [3], [4]. A number of environmental and behavioural factors, including vitamin D/UV [5] and smoking [6], are now viewed as causal factors. In addition to these, viral agents, particularly Epstein-Barr virus (EBV), human herpesvirus 6 (HHV6) [7] and human endogenous retroviruses (HERVs) [8], are thought to have an involvement in MS onset and progression.
This review discusses the role of EBV, HHV6 and HERVs in the onset and progression of MS. It focuses on the key epidemiological studies investigating the role of these viruses in disease, as well as interactions between these viruses and other risk factors, and the potential mechanisms underlying these associations. Finally, the potential of interventions targeting these agents and their modes of effect in the prevention and treatment of MS will be discussed.
Section snippets
What is Epstein-Barr virus?
EBV is a member of the human herpesvirus family and mainly infects B lymphocytes and epithelial cells. Viral parameters including Epstein-Barr nuclear antigen (EBNA) complex, which includes EBNA-1, 2, 3a, 3b, 3c and leader protein, viral capsid antigen (VCA), early antigen (EA) and EBV DNA (used to define viral load) are often used in EBV research. EA is observed at the early phase of EBV infection and only expressed during the lytic stage (active replication). EBV DNA can be found in serum at
What is human herpesvirus 6?
Another member of the herpesvirus family with a strong association with MS is human herpesvirus 6. HHV6 was first discovered in 1986 [87], and the primary infection is generally asymptomatic. HHV6 is also a double stranded DNA virus and can stay latent after the initial infection. Like EBV, anti-HHV6 IgG indicates a history of HHV6 infection, while anti-HHV6 IgM and HHV6 DNA are indicative of ongoing infection. Unlike EBV, HHV6 is comprised of two serotypes, HHV6A and HHV6B, each of which has
What are human endogenous retroviruses and multiple sclerosis-associated retrovirus?
Endogenous retroviruses originate from ancestral exogenous infecting viruses which were incorporated into the host genome and entered the germ line during evolution. Endogenous retroviruses make up nearly 8% of the human genome [116]. While through the process of evolution most endogenous retroviruses have become incomplete and lost their function, open reading frames still exist in some HERVs which encode functional proteins. While no longer capable of replication and lysis of host cells, some
Potential therapies that could influence the immune response to EBV/HHV6/HERVs in MS patients
Given the diverse evidence from epidemiology and laboratory research implicating the role of human herpesvirus infection(s) in MS, it has been assumed that efforts to prevent viral infection by vaccination or other prophylactic interventions could reduce MS risk or moderate its clinical course. Despite the tremendous potential for this point of intervention in MS prevention and treatment, relatively few studies aimed at treating MS from the perspective of viral infection have been conducted. To
Conclusions
A large number of epidemiological studies have ascertained the association between EBV and MS risk. The evidence for causality is well-supported within the present methodological framework to the extent that observational epidemiological outcomes can ascribe causality. Discrepancies in post-mortem and laboratory investigations of the role of EBV in MS patients are probably due to the diversity of sample quality and detection techniques, with most research inclined to support this association.
Conflict of interest
The authors declare that they have no conflict of interest.
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