Epstein–Barr Virus: More than Just an Infection

While typically associated with benign infectious mononucleosis, Epstein–Barr virus (EBV) is now recognized as a pivotal driver of complex immunopathological disorders. By shuttling between lytic replication and strategic latency programs, EBV reprograms B-cell biology to evade immune surveillance and disrupt homeostasis. Central to this pathogenesis is the viral protein EBNA1, which triggers autoimmunity through molecular mimicry with host antigens, including GlialCAM in multiple sclerosis (MS), keratin in rheumatoid arthritis, and nuclear proteins in systemic lupus erythematosus. These autoimmune responses are further exacerbated by bystander activation and epitope spreading, fueling chronic inflammation in Crohn’s disease, type 1 diabetes, and IgA nephropathy. EBV can also promote the development of lymphoproliferative disorders, whether in immunocompetent hosts or in the context of immunosuppression; however, the emergence of EBV-positive forms within diseases that are usually EBV-negative is closely linked to an underlying state of immunosuppression. Distinct from these chronic states, EBV-associated hemophagocytic lymphohistiocytosis (HLH) represents a critical hyperinflammatory emergency in which defective cytotoxicity leads to an uncontrolled T-cell- or NK-cell-driven cytokine storm; together with chronic active EBV disease (CAEBV), HLH disproportionately affects children, and both receive particular attention in this review. More recently, emerging but not yet consolidated evidence has also suggested a possible association between EBV reactivation and long COVID. Elucidating these diverse molecular interactions is essential for developing the next generation of targeted therapies and vaccine strategies aimed at mitigating the systemic impact of this virus.