KSHV latency control is stringently regulated by the interplay of two critical viral proteins that are expressed temporally during the life cycle of the virus. The human gammaherpesviruses KSHV and EBV both are predominantly latent in the infected cell although there are some levels of reactivation that persists in the population. In KSHV the immediate early transactivator Rta is packaged in the virion particle and is responsible for activating the major latent promoter responsible for transcription of the latent genes which include the latency associated nuclear antigen (LANA). Once LANA is expressed it functions as a multifaceted molecule which is responsible for the maintenance of the viral genome in the infected cells as well as the transcription regulation of Rta function which has been shown to autoactivate its own promoter during lytic replication. In esence these controls establish a finely tuned feedback loop for control of KSHV latency. In this application we will investigate the role of critical viral antigens responsible for latency control and determine the level of post-translational modification that is necessary for these regulatory events. We will also utilize a proteomic approach with recombinant KSHV cloned into the bacmid vector with wild type KSHV and a Rta knockout virus to identify the cellular components of the regulatory events. We will also determine the level of cellular control of the Rta promoter by determining the transcription modulators that are involved in chromatin remodeling at the specific sites targeted by the viral antigensto control latency and determine the extent at which the signaling pathway is utilized to establish latency and contribute to cell proliferation of KSHV infected cells.
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