Epstein–Barr virus, a widespread herpesvirus that establishes lifelong latency after primary infection, has emerged in serological and epidemiological studies as a strong and consistent risk factor for multiple sclerosis.

Emerging evidence indicates that Epstein–Barr virus can interact with several multiple sclerosis susceptibility loci to modify the transcriptional programmes and differentiation trajectories of B cells. Specifically, Epstein–Barr virus infection has been associated with the expansion of neuroinvasive, atypical B cells, which are enriched in inflamed CNS compartments in people with multiple sclerosis and exhibit a strong capacity to stimulate autoreactive T cells. Dysregulation of Epstein–Barr virus latency by B cells, together with subtle deficiencies in T-cell-mediated control of Epstein–Barr virus, might further amplify the effect of these B cell–T cell interactions and predispose individuals to multiple sclerosis.

These insights support the development of hypothesis-driven therapeutic strategies aimed at attenuating hyperactive autoimmune responses induced by Epstein–Barr virus and the autoimmune responses’ access to the CNS. Strategies under investigation include prophylactic and therapeutic vaccines; allogeneic cytotoxic T lymphocytes specific for Epstein–Barr virus and designed to eliminate virus-infected cells; antibody-based and chimeric antigen receptor T-cell-based therapies targeting B-cell subsets induced by Epstein–Barr virus and migrate into the CNS; and conventional antiviral treatments. Together, these approaches might open new perspectives for both prevention and treatment of multiple sclerosis. Furthermore, they might help to clarify whether Epstein–Barr virus infection influences not only susceptibility to multiple sclerosis, but also disease activity and disability accrual after disease onset.