Authors
Altas, B., Georgiou, P., Onisiforou, M., Zanos, P., Onisiforou, A.
Abstract
Background: Epstein-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. Methods: VirTarget 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. Results: Network 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. Conclusion: VirTarget 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.
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bioRxiv
The authors list and abstract were imported from bioRxiv on 06 Nov 2025.
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