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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE014153-01
Application #
6344461
Study Section
Special Emphasis Panel (ZDE1-YA (07))
Program Officer
Mangan, Dennis F
Project Start
2001-04-01
Project End
2005-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
1
Fiscal Year
2001
Total Cost
$229,527
Indirect Cost
Name
University of California Los Angeles
Department
Pharmacology
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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