VirTarget: Virus-Informed Pharmacogenomics Framework Identifies Immunotherapies That Mitigate Epstein-Barr Virus-Driven Dysregulation in Multiple Sclerosis

Abstract

BackgroundEpstein-Barr virus (EBV) is increasingly recognized as a central driver of multiple sclerosis (MS), yet current immunotherapies are selected without regard to their effects on EBV or EBV-MS genetic interactions. To address this gap, we developed VirTarget, the first virus-informed pharmacogenomics network framework that systematically evaluates approved MS immunotherapies with respect to EBV-driven pathogenesis and host genetic susceptibility risk. MethodsVirTarget integrates three complementary layers: (1) EBV-host interactomics, mapping viral-host protein- protein interactions within MS-relevant pathways; (2) host genetic susceptibility, linking MS-associated variants to EBV-targeted, therapy-modulated networks; and (3) transcriptomics directionality analysis, contrasting drug signatures with the convergent MS-EBV transcriptomic signature to classify therapies as reinforcers or reversers. ResultsNetwork analysis revealed substantial heterogeneity among therapies. Dimethyl fumarate showed the strongest and broadest engagement with the MS-EBV network, followed by natalizumab and interferons, while anti-CD20 antibodies and S1P modulators exerted the weakest effects. Genetic mapping highlighted convergence on key risk genes (HLA-DRB1, IL7R, IL2RA, CD40, TYR) directly targeted by EBV proteins within therapy-modulated pathways. Transcriptomic profiling stratified therapies into reinforcers (e.g., dimethyl fumarate, fingolimod, dexamethasone, interferon-{beta}1b) and reversers (e.g., prednisolone, cladribine, interferon-{beta}1a, rituximab), reflecting opposing influences on the MS{cap}EBV signature. Notably, multiple therapies reversed EBV-driven dysregulation of cytokine and innate immune pathways, suggesting their benefits extend in counteracting viral-mediated modulation of immune processes. ConclusionVirTarget provides the first systems-level, virus-informed comparative map of how MS immunotherapies engage with the MS-EBV network, intersect with MS genetic susceptibility risk, and modulate both MS- and EBV-related transcriptomic signatures. By revealing drug-specific patterns of viral pathway engagement and genetic convergence, this framework establishes a foundation for precision treatment strategies in MS, where therapeutic selection is informed by viral serostatus, host genetics, and system-level transcriptomic responses.