UNMASKING THE ROLE OF EPSTEIN–BARR VIRUS IN MULTIPLE SCLEROSIS: CLINICAL TYPE–SPECIFIC PATHOGENESIS AND VIRUS-INFORMED COMPARATIVE ANALYSIS OF IMMUNOTHERAPIES

Epstein–Barr virus (EBV) is increasingly recognized as a key environmental driver of multiple sclerosis (MS), yet its influence across disease clinical types remains largely unexplored. Moreover, current MS therapies rely on broad immunosuppression or immunomodulation, raising a fundamental paradox: if EBV contributes to MS pathogenesis, could dampening immune surveillance impair viral control and promote EBV-driven immune dysregulation rather than resolve it? To address these two questions, we developed VirTrack and VirTarget. VirTrack maps experimentally validated EBV–host protein interactions onto peripheral blood transcriptomes from clinically isolated syndrome, relapsing remitting, secondary progressive (SPMS), and primary progressive MS (PPMS) to resolve clinical type–specific viral effects, while VirTarget provides a systems-level, virus-informed pharmacogenomics framework to evaluate how approved MS immunotherapies engage EBV–host networks, intersect with MS genetic susceptibility risk, and modulate EBV- and MS-associated transcriptomic signatures. EBV engagement was strongest in early MS, targeting 13–18% of dysregulated genes and enriching for B-cell activation, Toll-like receptor signaling, and infection-like inflammatory pathways, whereas progressive clinical types showed fewer viral connections, with SPMS marked by suppression of vascular and cardiac repair pathways and PPMS by upregulation of vacuolar and lysosomal remodeling processes. Transcriptomic profiling separated therapies into reinforcers or reversers of the MS–EBV signature, including dimethyl fumarate and fingolimod as reinforcers and cladribine, interferon-β1a, and rituximab as reversers. These findings unmask EBV as a dynamic, stage-specific driver of MS and demonstrate that therapeutic effects are partly mediated through modulation of viral–host networks, supporting virus- and stage-informed precision treatment strategies.