Molecular Mechanisms of KSHV Latency Establishment and Maintenance.

Purpose of Review: This review summarizes results from recent studies that shed light on viral and cellular mechanisms that contribute to latency and persistence of Kaposi sarcoma-associated herpesvirus (KSHV). We discuss the initial molecular events of latency establishment starting from entry of the viral genome into the nucleus to how viral genomes are properly segregated when latently infected cells undergo mitosis. Finally, we discuss the critical role of the latency-associated nuclear antigen (LANA) in orchestrating these processes. Recent Findings: Upon entering the host-cell nucleus, naked viral DNA circularizes and rapidly associates with cellular histones and the transcription machinery. This permits a burst of viral gene expression including LANA which quickly recruits chromatin remodeling complexes and modifiers to organize the viral chromatin architecture. These events restrict transcription to the latency locus and switch the lytic genes to a repressed state that is poised for reactivation. Structural studies demonstrate that LANA assembly on the viral terminal repeats leads to the formation of higher order structures that stabilize the latent viral chromatin and impact how the viral episome is segregated during cell division. Summary: Understanding molecular mechanisms of latency establishment and maintenance provide insights into gammaherpesvirus biology and thus may reveal new strategies to prevent or treat KSHV-associated malignancies.