RNA Modifications and Their Role in Regulating KSHV Replication and Pathogenic Mechanisms

ABSTRACT Kaposi's sarcoma‐associated herpesvirus is an oncogenic gammaherpesvirus that plays a major role in several human malignancies, including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. The complexity of KSHV biology is reflected in the sophisticated regulation of its biphasic life cycle, consisting of a quiescent latent phase and virion‐producing lytic replication. KSHV expresses coding and noncoding RNAs, including microRNAs and long noncoding RNAs, which play crucial roles in modulating viral gene expression, immune evasion, and intercellular communication. Recent studies have highlighted the importance of RNA modifications, also known as the epitranscriptome, in regulating KSHV‐encoded RNAs, adding a novel layer of posttranscriptional control previously unknown. These RNA modifications, such as N 6 ‐methyladenosine, A‐to‐I editing, and N 4 ‐acetylcytidine, are involved in fine‐tuning KSHV gene expression during both latency and lytic replication. Understanding the role of RNA modifications in KSHV infection is essential for revealing new regulatory mechanisms and identifying therapeutic opportunities. Targeting these RNA modifications could serve as a strategy to disrupt key viral processes, offering promising insights into KSHV pathogenesis and therapeutic interventions.