Lifelong Epstein-Barr virus persistence as a stress test of ageing immune surveillance: From infectious mononucleosis to chronic active EBV disease and virus-associated malignancy

Epstein-Barr virus (EBV) infects most humans and persists lifelong within a dynamic equilibrium maintained by B-cell latency, cytotoxic T-cell control, NK-cell surveillance and humoral immunity. Ageing can remodel this equilibrium through thymic involution, contraction of the naive T-cell pool, accumulation of late-differentiated or exhaustion-like T-cell states, altered NK-cell function, B-cell dysfunction and chronic low-grade inflammation. Although cytomegalovirus has dominated discussions of persistent viral infection and immunosenescence, EBV offers a complementary model because it combines lifelong latency, intermittent reactivation, B-cell tropism, immune evasion and clinically diverse lymphoid, epithelial and hyperinflammatory disease contexts. This review conceptualizes EBV persistence as a functional stress test of ageing immune surveillance. Instead of assigning EBV a binary role as either a driver or passenger of immunosenescence, we argue that EBV may reveal and amplify deficits in viral containment, tissue immune ecology and inflammatory regulation. We integrate evidence from EBV-specific immune control, T-cell and NK-cell ageing, B-cell remodelling, inflammaging and EBV-associated diseases including IM, CAEBV, ENKTL, EBV-HLH, EBVMCU, EBV-positive DLBCL, PTLD, NPC and EBV-associated gastric cancer. These entities are organized as parallel immune-control states rather than as a chronological disease sequence: CAEBV and ENKTL illustrate T/NK-lineage containment failure, EBV-HLH links impaired cytotoxic reserve with inflammatory escalation, B-cell lymphoproliferative diseases illustrate surveillance loss, and epithelial cancers illustrate tissue-specific latency and local immune editing. A lifespan perspective on EBV may therefore clarify why some immune systems maintain resilient latency, whereas others lose EBV-control reserve and become permissive to reactivation, hyperinflammation, lymphoproliferation or malignancy.