Viral immune profiles in multiple sclerosis and HIV co-infection providing insights into antiretroviral treatment-associated immuno-remodeling

Multiple sclerosis (MS) and human immunodeficiency virus (HIV) rarely co-occur, suggesting HIV-mediated modulation of MS-related viral immunopathology. This multicentre cross-sectional study analyzed 14 individuals with MS + HIV (HIV → MS, n = 4; MS → HIV, n = 10), alongside HIV-positive individuals on antiretroviral therapy (ART, n = 21), MS ( n = 21; 18 on disease-modifying therapies DMTs), and healthy controls ( n = 21). IgG/IgM responses to Epstein–Barr virus (EBV), Cytomegalovirus (CMV), human herpesvirus-6 (HHV-6), and human endogenous retrovirus-W envelope (HERV-W env) were quantified by ELISA. HERV-W env expression in PBMC subsets was assessed by FACS/qPCR and flow cytometry (monoclonal antibody CALI222B). Discriminant function analysis (DFA) was used to evaluate a preliminary cohort classification. MS + HIV cohorts displayed higher CMV IgG seroprevalence (95–100% vs. 45% in MS; OR 24.4) and titres. EBNA-1 IgG prevailed in MS and MS + HIV (95–100% vs. 67% in HIV). HERV-W expression was reduced in HIV versus MS, particularly in HIV → MS. Exploratory DFA classified cohorts with 79.6% accuracy (CMV/EBNA-1 primary discriminators). Stepwise analysis identified CMV, EBNA-1, and EBV VCA IgG as main predictors, achieving 100% classification accuracy for MS + HIV (76.4% overall). CMV-dominated profiles distinguish MS + HIV comorbidity, with HIV/ART-associated suppression of EBV/HHV-6 humoral responses and HERV-W gene expression, suggesting an immune remodeling that may explain reduced MS prevalence among people living with HIV.