Kaposi's sarcoma (KS) is the most frequently occurring intraoral malignancy in AIDS patients. KS tumor cells are infected by human herpesvirus-8/Kaposi's sarcoma associated herpesvirus (HHV-8/KSHV). HHV-8 virions are shed into the saliva of AIDS patients. Herpesviruses exhibit two distinct life cycle phases, latency and lytic replication. Viral latency is directly associated with the proliferation of infected cells with limited viral gene expression and is refractory to any antiviral drugs. Most tumor cells in Kaposi's sarcoma lesions are infected by HHV-8 in the latent phase. During the lytic phase, or upon reactivation from latency, expression of all viral genes produces virions and results in death of the host cell, meanwhile providing targets for antiviral drugs such as Gancyclovir. A viral immediate-early gene, Rta, the replication and transcription activator of HHV-8, was recently identified by Dr. Sun. Rta is necessary and sufficient for disrupting latency and initiation of HHV-8 lytic replication. Furthermore, Rta can autostimulate its own gene expression, and is therefore a sensitive molecular switch in the HHV-8 life cycle. Dr. Sun's study of Rta leads him to propose the hypothesis that intentional induction of lytic replication of HHV-8 in KS tumor cells will lead to lysis of infected tumor cells and destruction of the tumor lesion.
The specific aims of his proposal are: 1) to further define the mechanism controlling the expression of Rta; and 2) to develop multiple approaches to induce HHV-8 lytic replication of HHV-8 and lysis of KS tumor cells in the presence of Gancyclovir.
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