HHV-6 and EBV reactivation in relapsing remitting multiple sclerosis: Disability, progression, and inflammation links

Reactivation of human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) is observed in multiple sclerosis (MS). This study investigates immunoglobulins (Ig)G, IgM, and IgA responses to EBV nuclear antigen EBNA (peptide 386-405), HHV-6 (peptide 300-322) and EBV (peptide 243-268) deoxyuridine-triphosphatase (dUTPase), and different immune profiles in 58 patients with relapsing remitting MS (RRMS) compared to 60 healthy controls. IgA/IgG/IgM were measured utilizing enzyme-linked immunosorbent assays, and cytokines, chemokines, and growth factors utilizing multiplex immunoassays. RRMS patients showed significantly increased IgG, IgA, and IgM responses to all three viral antigens. IgG and IgM to HHV-6 dUTPase discriminated RRMS patients from controls with 91.5% accuracy. Neural network analysis combining EBV-dUTPase antibodies and immune profiles yielded 97.1% predictive accuracy. IgG/IgM responses to dUTPases correlated with Expanded Disability Status Scale/MS Severity Score and aberrations in M1 macrophage, Th17 profiles, and overall immune activation. HHV-6 and EBV reactivation contribute to RRMS through cytokine-driven immune activation.