Epstein-Barr virus infection fundamentally alters the antigen presentation machinery in B cells carrying the HLA-DR15 genetic variant, causing them to display myelin basic protein fragments identical to those found in multiple sclerosis brain tissue. The virus reprograms both the transcriptome and immunopeptidome, with infected B cells presenting specific MBP peptides (MBP78-90 and MBP83-90) that trigger CD4+ T cell responses in MS patients. This molecular hijacking provides the first direct mechanistic explanation for why two major MS risk factors—EBV exposure and HLA-DR15 inheritance—work synergistically to trigger autoimmune demyelination. The finding resolves a decades-old puzzle in MS research, where epidemiological studies consistently linked EBV infection to MS onset, particularly in individuals with certain HLA variants, but the underlying biological mechanism remained elusive. This viral reprogramming of antigen presentation creates a molecular mimicry scenario where the immune system, primed to fight EBV, mistakenly attacks the brain's protective myelin sheath. The discovery opens therapeutic avenues targeting either EBV reactivation or the specific peptide-HLA interactions driving autoimmunity, potentially offering more precise interventions than current broad immunosuppressive treatments.