The regulation of KSHV lytic reactivation is predominantly controlled by the immediate early transactivators of the beta and gamma genes. These genes are responsible for replication of the viral genome and synthesis of the viral core proteins for production of viral progeny. Recently, it has been shown that the latency associated nuclear antigen (LANA) can modulate and shut down the expression of Rta by repressing the activation mediated by cellular factors that bind to cis acting elements as well as the autoactivation by Rta of its own promoter. This study investigates the role of LANA in maintenance of KSHV reactivation control and the requirement for post-translational modification of Rta and LANA for a functional role in this controlled feedback loop. The association with cellular proteins including the association with the transcriptional represser RBP-Jk and HDACs will be further investigated. We will also identify the cellular and viral proteins involved in regulation of this reactivation control which is associated with Rta and LANA using a number of biochemical and proteomics approaches. We will also determine the coactivators and corepressors involved in this regulatory loop which controls the expression of Rta and LANA in the context of KSHV infection and the regulation of the KSHV lytic cycle by using the upstream activator of RBP-Jk for activation of the immediate early promoter if expressed from a heterologous expression system. We will also use strategies for targeted downregulation of Rta to determine if KSHV reactivation can be bypassed in the absence of Rta expression.
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