2025/11/04 by Bekir Altas, Polymnia Georgiou, Marios Onisiforou +2 · 1 voice
Medicine · Biochemistry, Genetics and Molecular Biology · #Multiple Sclerosis Research Studies #vaccines and immunoinformatics approaches #Viral-associated cancers and disorders
paper · doi:10.1101/2025.11.03.686445
openalex publication_date 2025/11/04 · openalex created_date 2025/11/05 · openalex updated_date 2026/07/14
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-β1b) and reversers (e.g., prednisolone, cladribine, interferon-β1a, rituximab), reflecting opposing influences on the MS∩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.