: Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8 (KSHV/HHV-8) is an etiologic agent of Kaposi's sarcoma (KS), multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL). HHV-8 remains latent in the majority of tumor cells, but undergoes reactivation in a small percentage of tumor cells in KS. A viral immediate-early gene product, Rta (lytic replication and transcription activator), has been found to be sufficient and necessary to disrupt latency and initiate viral lytic gene expression in PEL cell lines latently infected by HHV-8. Rta also activates the expression of virally encoded homologues of interleukin 6 (IL-6) and macrophage inflammatory protein (MIP) lalpha, which are believed to play important roles in the pathogenesis of KS, MCD and PEL. The dynamic balance between latency and lytic replication plays a critical role in determining the pathogenic outcome of a viral infection. Therefore, it is critical for us to understand the mechanism that controls the switch between latency and lytic replication. Our initial finding of the pivotal role of Rta in the HHV-8 life cycle warrants further studies of the structure and function of Rta. Current data suggest the hypothesis that Rta activates viral lytic replication by trans-activating gene expression in an ordered cascade. Our objective is to dissect this cascade and the mechanism by which Rta activates the transcription of downstream genes. Accordingly, the Specific Aims of this proposal are to: 1. Identify genes directly activated by Rta and define the sequence binding specificity of Rta; 2. Define the amino acid sequences of Rta required for its trans-activation function. Understanding the mechanism of the switch from latency to lytic replication will aid in the development of new therapeutic strategies for diseases associated with HHV-8 infection. By regulating the expression and/or function of Rta, we can either suppress viral replication to inhibit the spread of viral infection or induce viral lytic replication to destroy infected tumor cells.
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