Human genetic and immunological determinants of Epstein-Barr virus-driven disease

Epstein-Barr virus (EBV) infects the vast majority of humans and establishes lifelong latency, yet causes disease in only a minority of individuals, underscoring the critical role of host determinants. This review examines the recent advances in how host genetics and immunological variation shape susceptibility to EBV across three major disease contexts. First, inborn errors of immunity have revealed essential CD8⁺ T-cell pathways governing control of EBV-driven B-cell lymphoproliferative disorders, through antigen recognition, co-stimulation, and cytokine signaling. EBV-positive T- and natural killer-cell lymphoproliferative disorders represent a second, more complex disease spectrum that arises through a multistep pathogenesis involving atypical viral entry, impaired immune control and homeostasis, and acquisition of somatic genetic alterations. Finally, we review new mechanistic evidence linking EBV to the development of autoimmune diseases, in particular multiple sclerosis and systemic lupus erythematosus, highlighting how EBV-mediated cell reprogramming amplifies immune dysregulation and self-reactivity. Together, these conditions establish EBV-associated diseases as powerful models for uncovering the complex genetic and immunological principles governing antiviral immunity and immune dysregulation.