Reactivation of Kaposi's sarcoma-associated herpesvirus Gammaherpesviruses establish latency, which is directly linked to cellular transformations and malignancies. Epstein-Barr virus (EBV) is associated with non-Hodgkin's lymphoma and oral hairy leukoplakia in AIDS patients, as well as nasopharyngeal carcinoma in South Asia and lymphoproliferation diseases in transplant patients. Kaposi's sarcoma-associated herpesvirus/Human herpesvirus-8 (KSHV/HHV-8) is the etiologic agent of Kaposi's sarcoma (KS), the most common malignancy in AIDS patients. These viruses express all of their viral genes to produce virions during the lytic phase or upon reactivation from latency, rendering them vulnerable to antiviral drugs such as Gancyclovir. However, in tumor cells, these viruses are in the latent phase and are refractory to currently available antiviral drugs. Our previous study identified Rta as an immediate-early viral gene of KSHV. Rta functions as the replication and transcription activator of the KSHV lytic cycle. As a molecular switch, Rta expression is necessary and sufficient to disrupt latency and initiate viral lytic replication. Therefore, defining the mechanism that regulates Rta expression and activity is crucial for understanding the molecular switch of the KSHV life cycle. Both viral and cellular factors regulate the expression of Rta. Little is known about the cellular mechanisms controlling Rta expression. High throughput genetic screening approaches are being used to systematically identify cellular genes that enhance KSHV reactivation and their interactions with the Rta promoter of the viral genome. The study will define cellular pathways that regulate KSHV reactivation. Specifically, we will determine how the Dopamine receptors and related signaling pathways induce KSHV reactivation via activation of Rta expression and upregulation of Rta activity. Not only does this study address a fundamental question in herpesvirus biology, the knowledge gained from it will be instrumental for developing new potential therapeutic approaches. It could lead to treatments against KSHV-infected tumors by allowing the intentional induction of viral lytic gene expression in latently infected tumor cells. Thus, this mechanistic study of the herpesvirus life cycle will have direct clinical applications for cancer patients.
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