Researchers have long believed that multiple sclerosis (MS) risk factors include infectious agents including Epstein-Barr virus (EBV). Recent studies have added weight to this hypothesis. This paves the way for future potential interventions, but questions around how EBV might cause autoimmune diseases including MS remain unclear.
Ahead of MSMilan2023, we look at the hot topic of EBV in MS, what we have learnt so far, the questions still unanswered, and how this year’s annual congress will add to the fast-evolving debate.
What is EBV?
EBV is a ubiquitous herpesvirus. More than 90% of the world’s population have evidence of EBV infection. Spread is primarily through infected saliva. Like all herpesviruses, it is a lifelong infection.
While childhood infection is usually subclinical, infection in adolescence has been associated with infectious mononucleosis. EBV has been associated with numerous cancers, including nasopharyngeal carcinoma, subtypes of Hodgkin and non-Hodgkin lymphomas, BV-associated gastric carcinoma, natural killer (NK)/T cell lymphomas, and leiomyosarcomas. Furthermore it is a cause of fatal lymphoproliferative disorders in various immunosuppressive conditions.
It has also long been suspected of playing an important role in the development of MS.
The evidence so far
In recent years, large, population-based studies have suggested that infection with EBV is a necessary prerequisite for developing autoimmune diseases, and thus also MS.
One recent study of particular note monitored more than 10 million people on active duty in the US military over 20 years, 955 of whom were diagnosed with MS during service. The team analysed serum samples taken biennially by the military to determine EBV status and the relationship between EBV infection and MS onset. They found that the risk of MS increased 32-fold after EBV infection. Serum neurofilament light chain (sNfL), a biomarker of disease activity, increased after infection with EBV, but not with other viruses. The findings, said the authors, could not be explained by any other known risk factor and suggested that EBV was a crucial step on the pathway to developing MS.
In a press release soon after the results were published in January last year, Professor Alberto Ascherio, senior author of the study, said: “The hypothesis that EBV causes MS has been investigated by our group and others for several years, but this is the first study providing compelling evidence of causality. This is a big step because it suggests that most MS cases could be prevented by stopping EBV infection and that targeting EBV could lead to the discovery of a cure for MS.”
Such studies have added EBV to the complex web of MS risk factors. Current thinking on aetiology involves the interplay of genetic susceptibility factors primarily in immune system-directing genes, and environmental factors. These include sun exposure and vitamin D, smoking, obesity – and EBV.
Yet while various studies have demonstrated that EBV infection is a likely prerequisite of autoimmune disease, how we translate this growing body of evidence into improved clinical outcomes remains unclear.
A review of the evidence published in August said that how EBV, which tends to cause benign, latent infection, and promotes cancer and autoimmune disease in at-risk populations was “not fully understood”.
In the context of MS development, some of the most pressing outstanding questions include whether EBV-infected cells or viral products act within the central nervous system (CNS) or indirectly, through inflammatory events in the periphery, and how autoreactive immune cells and antibodies form and accumulate in the CNS.
Severity and duration of infection, as well as initial immune response and genetic risk alleles, are all likely to play a role, said the authors, adding that the knowledge that EBV is a likely driver of inflammatory autoimmune disease provided a target for future therapies.
“Currently, there is no way to prevent or treat EBV infection, but an EBV vaccine or targeting the virus with EBV-specific antiviral drugs could ultimately prevent or cure MS,” said Prof Ascherio, who will speak about his study during the 9th Joint ECTRIMS-ACTRIMS Meeting, in October.
The congress session, MS and EBV – implications for management and treatment, will bring delegates fully up to date with all the latest research and thinking on this hot topic area.
Prof Ascherio will be joined by Prof Christian Münz, of the University of Zürich, Switzerland, and Prof William H. Robinson, from Stanford University, USA. The speakers, who have published extensively on the relationship between EBV and MS, will also participate in a discussion and question and answer session.
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 Hoover, K., & Higginbotham, K. (2004). Epstein Barr Virus. Infections of the central nervous system. Philadelphia, PA: Lippincott Williams & Wilkins, 175-183.
 Soldan, S. S., & Lieberman, P. M. (2023). Epstein–Barr virus and multiple sclerosis. Nature Reviews Microbiology, 21(1), 51-64.
 Bjornevik, K., Cortese, M., Healy, B. C., Kuhle, J., Mina, M. J., Leng, Y., … & Ascherio, A. (2022). Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science, 375(6578), 296-301.
 Harvard TH Chan School of Public Health. (2022) Epstein-Barr virus may be leading cause of multiple sclerosis. Available at: https://www.hsph.harvard.edu/news/press-releases/epstein-barr-virus-may-be-leading-cause-of-multiple-sclerosis/
Last accessed: 2 June 2023