Epstein-Barr virus and human MiRNAs crosstalk: orchestrating latency, lytic cycle, and immune system modulation

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that establishes lifelong latency in its host and is associated with a range of malignancies and immune-related disorders. This review examines the complex interactions between EBV and microRNAs (miRNAs), small, non-coding RNAs that regulate gene expression at the post-transcriptional level. It focuses on EBV-encoded miRNAs derived from the BHRF1 and BART clusters, detailing their distinct functions during different latency phases and viral reactivation. These miRNAs facilitate immune evasion, modulate cell cycle progression, apoptosis, and differentiation, and promote cellular environments that favor viral persistence and oncogenesis. EBV also disrupts host miRNA networks, altering gene expression and immune regulation, which contributes to tumor development in diseases such as Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, and post-transplant lymphoproliferative disorders, and has additionally emerged as a leading etiological factor in multiple sclerosis. Furthermore, the review highlights how viral and host miRNAs jointly modulate immune checkpoints, antiviral defense mechanisms, and the tumor microenvironment. It concludes by summarizing recent progress in miRNA-based diagnostics and therapeutics, underscoring their potential for advancing personalized medicine in EBV-associated pathologies.