PERSISTENCE OF EPSTEIN BARR VIRUS INFECTION IN MULTIPLE SCLEROSIS BRAIN: ALTERED CYTOTOXIC IMMUNE RESPONSE AND IMMUNE EVASION STRATEGIES

PERSISTENCE OF EPSTEIN BARR VIRUS INFECTION IN MULTIPLE SCLEROSIS BRAIN: ALTERED CYTOTOXIC IMMUNE RESPONSE AND IMMUNE EVASION STRATEGIES Lucia Benincasa, Barbara Rosicarelli, Caterina Veroni, Barbara Serafini Department of Neuroscience, Istituto Superiore di Sanità, Rome, Italy. Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system resulting from complex interactions between known susceptibility genes, lifestyles and environmental factors. Among the latter, Epstein-Barr virus (EBV) infection shows the strongest association with MS, and has been demonstrated to be a prerequisite for disease development. The effectiveness of drugs targeting B-cells, the latent EBV reservoir, strengthens the view that reducing EBV load, and therefore the cellular immune response to EBV, has beneficial effects on people with MS. Despite these evidences, the pathological mechanisms linking EBV to MS pathology, and favouring the persistence of the virus in the MS brain, are still unclear. To explore the effectiveness of the EBV immune control in MS, we performed careful neuropathological studies of the presence and functional characteristics of tissue resident memory (Trm) T cells, and of the involvement of the viral immune evasion mechanism based on the PD-1/PD-L1 axis, in post-mortem brain tissue donated by persons with secondary progressive disease. We found: presence EBV-infected B cells and EBVspecific CD8 T cells in the inflammatory infiltrates; alterations in the cytotoxic functionality of the Trm cells; expression of molecules related to the viral immune evasion mechanisms on B and T cells invading MS brain. These evidences suggest that EBV could use the PD-1/PDL1 axis to establish a persistent infection in the MS brain, that induces a continuos, inefficient but highly detrimental, intracerebral antiviral immune response. Our data support a model of MS as “a rare neurological complication of a very common viral infection” in which EBV is the main driver of the disease. This research was supported by FISM - Fondazione Italiana Sclerosi Multipla - cod. 2022/RSingle /006 and financed or co-financed with the ‘5 per mille’ public funding, and by European Union within BEHIND-MS project.