Epigenetic Regulation of the Epstein–Barr Virus Latent–Lytic Switch

ABSTRACT

Epstein–Barr virus (EBV) establishes lifelong latency in humans, yet sporadically reactivates into a productive lytic cycle that enables viral propagation. The lytic phase is critical for sustaining life‐long persistence and also contributes to oncogenesis by fostering cellular environments that support EBV‐associated malignancies. EBV lytic reactivation has long been understood as a complex process shaped by the integration of multiple, largely host‐derived signals. Recent advances in genome‐wide CRISPR screening, single‐cell transcriptomics, and integrative multi‐omic analyses have substantially expanded this framework, adding rich and unexpected molecular detail to how epigenetic repression, transcriptional control, metabolic adaptation, and immune–microenvironmental cues converge to regulate the latent–lytic transition. This review synthesizes recent discoveries that refine our understanding of the molecular logic of EBV reactivation and discusses how these insights are shaping new therapeutic approaches.