Regulation of expression, mode of action and downstream targets of orf50 protein in KSHV lytic cycle activation

Kaposi's sarcoma-associated herpesvirus (KSHV), human herpesvirus 8, is a gamma class herpesvirus associated with at least three human malignancies which are increased in prevalence in patients with HIV/AIDS: Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. In common with all herpesviruses, KSHV can exist in a latent or a lytic state. Since both latent and lytic viral gene products play essential roles in the viral life cycle and in oncogenesis by KSHV, understanding the control of the latent to lytic switch provides important insights into KSHV pathogenesis. The switch between latency and lytic replication of KSHV is initiated by a single multifunctional protein encoded by open reading frame 50 (ORF50) of the viral genome. During latency the ORF50 gene is repressed. When the ORF50 protein, also called RTA (replication and transcription activator) is expressed, it is sufficient to induce the complete viral lytic replication cycle. Here we discuss the regulation of the ORF50 promoter, summarize recent efforts to characterize the molecular actions of ORF50 protein, and describe how viral targets of ORF50 protein may contribute to KSHV replication and pathogenesis.