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  • Review Article
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Epstein–Barr virus as a leading cause of multiple sclerosis: mechanisms and implications

Abstract

Epidemiological studies have provided compelling evidence that multiple sclerosis (MS) is a rare complication of infection with the Epstein–Barr virus (EBV), a herpesvirus that infects more than 90% of the global population. This link was long suspected because the risk of MS increases markedly after infectious mononucleosis (symptomatic primary EBV infection) and with high titres of antibodies to specific EBV antigens. However, it was not until 2022 that a longitudinal study demonstrated that MS risk is minimal in individuals who are not infected with EBV and that it increases over 30-fold following EBV infection. Over the past few years, a number of studies have provided clues on the underlying mechanisms, which might help us to develop more targeted treatments for MS. In this Review, we discuss the evidence linking EBV to the development of MS and the mechanisms by which the virus is thought to cause the disease. Furthermore, we discuss implications for the treatment and prevention of MS, including the use of antivirals and vaccines.

Key points

  • In a longitudinal study that followed individuals seronegative for Epstein–Barr virus (EBV) over time, multiple sclerosis (MS) risk increased more than 30-fold after EBV infection. The results are unlikely to be explained by reverse causation or confounding factors.

  • Among individuals who are EBV positive, those with a history of infectious mononucleosis or with high antibody titres against EBV nuclear antigens have an increased risk of developing MS.

  • Several mechanisms have been proposed to explain the link between EBV and MS, including molecular mimicry and an altered immune response to poorly controlled EBV infection.

  • Vaccines that might prevent EBV infection are currently being developed. If effective, these vaccines would be expected to prevent most MS cases.

  • Targeting EBV with therapeutic vaccines or antiviral drugs could represent a novel treatment strategy for MS.

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Fig. 1: MS risk factors and disease course.
Fig. 2: Mechanistic links between EBV infection and MS.
Fig. 3: EBV-targeted strategies to prevent or ameliorate MS.

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Acknowledgements

C.M. is supported by Cancer Research Switzerland (KFS-4962-02-2020), HMZ ImmunoTargET of the University of Zurich, the Sobek Foundation, the Swiss Vaccine Research Institute, the Swiss MS Society (2021-09), the Vontobel Foundation and the Swiss National Science Foundation (310030_204470/1, 310030L_197952/1 and CRSII5_180323). J.I.C. is supported by the intramural research programme of the National Institute of Allergy and Infectious Diseases.

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J.I.C. is named as an inventor on patent applications for Epstein–Barr virus vaccines, which have been filed by the NIH. A.A. has received an honorarium as a speaker from Moderna. K.B. and C.M. declare no competing interests.

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Bjornevik, K., Münz, C., Cohen, J.I. et al. Epstein–Barr virus as a leading cause of multiple sclerosis: mechanisms and implications. Nat Rev Neurol 19, 160–171 (2023). https://doi.org/10.1038/s41582-023-00775-5

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