The Epstein-Barr Virus in Classical Hodgkin Lymphoma: Pathogenesis, Immunobiology, and Therapeutic Implications

Classical Hodgkin lymphoma (cHL) is a unique B cell malignancy characterised by the presence of Hodgkin/Reed-Sternberg (HRS) cells within an extensive inflammatory microenvironment. In approximately 40% of cases- particularly in the mixed cellularity subtype-HRS cells are infected with the Epstein-Barr virus (EBV). EBV-positive cHL displays a restricted pattern of viral gene expression (latency II), with functional contributions from EBNA1, LMP1, and LMP2A/B, as well as some non-coding RNAs. This review synthesises current knowledge on the role of EBV in the pathogenesis of cHL. It provides an overview of molecular and immunological distinctions between EBV-positive and EBV-negative cHL, highlighting differences in host genomic alterations, immune evasion strategies, and tumour microenvironment composition. EBV+ cHL demonstrates a relatively lower mutational burden but harnesses viral proteins to subvert immune surveillance, recruit regulatory immune subsets, and upregulate checkpoint ligands, such as PD-L1. We also discuss the prognostic significance of EBV in cHL, its epidemiological associations with HLA polymorphisms, and emerging EBV-directed immunotherapies- including virus-specific T cell transfer and engineered TCR approaches.