The case for targeting latent and lytic Epstein-Barr virus infection in multiple sclerosis

Epstein-Barr virus (EBV) is strongly associated with multiple sclerosis (MS). It is likely to play a causal role in the pathogenesis of MS, possibly via triggering autoimmunity through molecular mimicry, autoantigenic presentation or immune dysregulation. Alternatively, evidence supports a direct role for EBV in driving MS disease activity via latent-lytic infection cycling either within the CNS or the periphery. We highlight the recent immunological and virological findings supporting the role of active EBV infection in MS, supporting an evaluation of anti-EBV strategies as potential treatments for MS. Anti-EBV strategies include CNS penetrant small molecule anti-viral agents targeting latent and lytic infection, and immunotherapies. Immunotherapies include EBV-specific autologous or allogeneic cytotoxic T cells (CTLs) and therapeutic EBV vaccines and/or immune checkpoint inhibitors to rejuvenate and boost endogenous EBV-targeted CTL responses. In parallel, several licensed MS disease-modifying therapies may work via mechanisms targeting EBV directly or indirectly. B-cell depleting therapies have been shown to have anti-EBV activity; additionally, new strategies to target intrathecal B cells, plasmablasts and plasma cells are being explored, including high-dose anti-CD20 therapy, cladribine, proteasome inhibitors, BTK inhibitors, CNS-penetrant anti-CD20/CD19 monoclonal antibodies and CD19-targeted CAR T cells. Innovative trial designs for proof-of-concept studies to test EBV antivirals and immunotherapies in MS are needed to catalyse a wave of drug development targeting EBV as a therapeutic strategy to prevent or treat MS.