Elsevier

Journal of the Neurological Sciences

Volume 372, 15 January 2017, Pages 239-249
Journal of the Neurological Sciences

Review Article
Association between human herpesvirus & human endogenous retrovirus and MS onset & progression

https://doi.org/10.1016/j.jns.2016.11.060Get rights and content

Highlights

  • Epstein-Barr virus has been established as one of the causal factors in MS onset, but its role in MS progression less certain.

  • Human herpesvirus 6 shows a closer connection with the disease activity.

  • Interesting recent work on human endogenous retroviruses shows associations with both the development and progression of MS.

  • Antiviral treatments could become promising in the future.

Abstract

This review discusses the role of Epstein-Barr virus (EBV), human herpesvirus 6 (HHV6) and human endogenous retroviruses (HERVs) in the onset and progression of multiple sclerosis (MS). Although EBV has been established as one of the causal factors in MS onset, its role in MS progression is still uncertain. Moreover, interactions between EBV and other risk factor on MS development still need more investment. With less consistent evidence than EBV, HHV6 has also been implicated in the pathogenesis of MS; moreover, it showed a closer connection with the disease activity. Recent studies found that HERVs were associated with the development and progression of MS. Some antiviral treatments have shown promise for clinical interventions in the future. Future studies are yet needed to fully clarify the role of these agents in MS onset and disease course and the modes by which they realise these effects.

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.

References (155)

  • A.E. Handel et al.

    Smoking and multiple sclerosis: an updated meta-analysis

    PLoS One

    (2011)
  • T. Christensen

    Human herpesviruses in MS

    Int. MS J.

    (2007)
  • T. Christensen

    HERVs in neuropathogenesis

    J. NeuroImmune Pharmacol.

    (2010)
  • W. Henle et al.

    Antibody responses to Epstein-Barr virus-determined nuclear antigen (EBNA)-1 and EBNA-2 in acute and chronic Epstein-Barr virus infection

    Proc. Natl. Acad. Sci. U. S. A.

    (1987)
  • G.W. Bornkamm et al.

    Molecular virology of Epstein-Barr virus

    Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci.

    (2001)
  • O.A. Odumade et al.

    Progress and problems in understanding and managing primary Epstein-Barr virus infections

    Clin. Microbiol. Rev.

    (2011)
  • B. Savoldo et al.

    Generation of EBV-specific CD4 + cytotoxic T cells from virus naive individuals

    J. Immunol. (Baltimore, Md : 1950)

    (2002)
  • E. Cesarman

    Gammaherpesviruses and lymphoproliferative disorders

    Annu. Rev. Pathol.

    (2014)
  • J. Pakpoor et al.

    The risk of developing multiple sclerosis in individuals seronegative for Epstein-Barr virus: a meta-analysis

    Mult. Scler.

    (2013)
  • A. Ascherio et al.

    Epstein-Barr virus and multiple sclerosis

    Epidemiology

    (2000)
  • J. Pakpoor et al.

    Epstein-Barr virus is a necessary causative agent in the pathogenesis of multiple sclerosis: yes

    Mult. Scler.

    (2013)
  • R.M. Lucas et al.

    Epstein-Barr virus and multiple sclerosis

    J. Neurol. Neurosurg. Psychiatry

    (2011)
  • E.L. Thacker et al.

    Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis

    Ann. Neurol.

    (2006)
  • A.E. Handel et al.

    An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis

    PLoS One

    (2010)
  • T.R. Nielsen et al.

    Multiple sclerosis after infectious mononucleosis

    Arch. Neurol.

    (2007)
  • A.J. McMichael et al.

    Does immunosuppressive ultraviolet radiation explain the latitude gradient for multiple sclerosis?

    Epidemiology

    (1997)
  • S.V. Ramagopalan et al.

    Relationship of UV exposure to prevalence of multiple sclerosis in England

    Neurology

    (2011)
  • S. Simpson et al.

    Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis

    J. Neurol. Neurosurg. Psychiatry

    (2011)
  • A. Alonso et al.

    Temporal trends in the incidence of multiple sclerosis: a systematic review

    Neurology

    (2008)
  • G. Disanto et al.

    Epstein-Barr virus, latitude and multiple sclerosis

    Mult. Scler.

    (2013)
  • W. Grant

    Latitude and multiple sclerosis prevalence: vitamin D reduces risk of Epstein–Barr virus infection

    Mult. Scler.

    (2010)
  • A. Lossius et al.

    Season of infectious mononucleosis and risk of multiple sclerosis at different latitudes; the EnvIMS study

    Mult. Scler.

    (2013)
  • A. Ascherio et al.

    Environmental risk factors for multiple sclerosis. Part I: the role of infection

    Ann. Neurol.

    (2007)
  • Y.H. Almohmeed et al.

    Systematic review and meta-analysis of the sero-epidemiological association between Epstein Barr virus and multiple sclerosis

    PLoS One

    (2013)
  • A. Ascherio et al.

    Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study

    JAMA

    (2001)
  • P. Sundstrom et al.

    An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study

    Neurology

    (2004)
  • L.I. Levin et al.

    Temporal relationship between elevation of epstein-barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis

    JAMA

    (2005)
  • G.N. DeLorenze et al.

    Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up

    Arch. Neurol.

    (2006)
  • L.I. Levin et al.

    Multiple sclerosis and Epstein-Barr virus

    JAMA

    (2003)
  • C.E. Cocuzza et al.

    Quantitative detection of epstein-barr virus DNA in cerebrospinal fluid and blood samples of patients with relapsing-remitting multiple sclerosis

    PLoS One

    (2014)
  • J.W. Lindsey et al.

    Quantitative PCR for Epstein-Barr virus DNA and RNA in multiple sclerosis

    Mult. Scler.

    (2009)
  • R.M. Lucas et al.

    Current and past Epstein-Barr virus infection in risk of initial CNS demyelination

    Neurology

    (2011)
  • S. Simpson et al.

    EBV & HHV6 reactivation is infrequent and not associated with MS clinical course

    Acta Neurol. Scand.

    (2014)
  • K. Wandinger et al.

    Association between clinical disease activity and Epstein-Barr virus reactivation in MS

    Neurology

    (2000)
  • O. Torkildsen et al.

    Epstein-Barr virus reactivation and multiple sclerosis

    Eur. J. Neurol.: the official journal of the European Federation of Neurological Societies.

    (2008)
  • D. Buljevac et al.

    Epstein-Barr virus and disease activity in multiple sclerosis

    J. Neurol. Neurosurg. Psychiatry

    (2005)
  • R.A. Farrell et al.

    Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI

    Neurology

    (2009)
  • D.F. Angelini et al.

    Increased CD8 + T cell response to Epstein-Barr virus lytic antigens in the active phase of multiple sclerosis

    PLoS Pathog.

    (2013)
  • M.P. Pender et al.

    Epstein-Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis

    Mult. Scler.

    (2014)
  • M. Castellazzi et al.

    Epstein-Barr virus specific antibody response in multiple sclerosis patients during 21 months of natalizumab treatment

    (2015)
  • Cited by (18)

    • The dysregulation of autophagy and ER stress induced by HHV-6A infection activates pro-inflammatory pathways and promotes the release of inflammatory cytokines and cathepsin S by CNS cells

      2022, Virus Research
      Citation Excerpt :

      MS is indeed characterized by a progressive demyelination, process in whose triggering viral infection may also be involved (Mechelli et al., 2021). There are indeed several reports investigating the possible link between Herpesvirus infection and MS and, among those, a particular attention has been given to Epstein Barr virus (EBV) (Bjornevik et al., 2022; Robinson and Steinman, 2022), which remains the top candidate as causal agent for such disease, HHV-6A/B (Leibovitch and Jacobson, 2014) and Human Endogenous Retrovirus (HERVs) (Tao et al., 2017), viruses that could also work together in promoting MS (Komaroff et al., 2020). Interestingly, as HHV-6 encodes for U24 membrane protein shares some amino acids with MBP protein, in a previous study we have investigated a possible T cell cross-reactivity between HHV-6A and MBP (Cirone et al., 2002).

    • Vitamin D and multiple sclerosisAn update

      2017, Multiple Sclerosis and Related Disorders
      Citation Excerpt :

      Moreover, vitamin D supplementation appears to decrease the anti-EBNA1 serum level (Røsjø et al., 2017), which might be a beneficial effect. Infections with human herpes virus of type 6 or human endogenous retrovirus could also be MS risk factors and/or factors worsening the disease (Tao et al., 2017). By contrast, the accumulation of numerous common infections and/or infestations with parasites during childhood appears to be protective from the risk of autoimmune diseases occurring later, including MS (Correale and Gaitán, 2015; Gustavsen et al., 2014): this constitutes the ‘hygiene’ hypothesis, in which a particular development of the protective Tregs could be favorable.

    View all citing articles on Scopus
    View full text