Project Summary Abstract After 25 years there is still is no adequate animal model for Kaposi Sarcoma (KS), which is the most common cancer in people living with HIV/AIDS world-wide. Notably, KS develops even in HIV-infected person with normal CD4 counts and no detectable HIV viral load, as well as in HIV-negative persons – so called classic KS. The KS-associated herpesvirus (KSHV) is necessary for KS. Rather than focusing on one specific viral gene, we inserted the entire 138,146 bp KSHV viral genome into transgenic mice. These develop angiosarcoma and the KSHV genes are expressed in the tumor. This proposal seeks to understand the mechanism of KS tumorigenesis and to study known and novel drug candidates. This proposal responds to NCI provocative question six: “Can novel in vitro and in vivo models of HIV/AIDS-associated malignancies be developed to study their development, pathogenesis, and the potential evaluation of novel treatments for common HIV/AIDS-associated malignancies?”