Project 3 Abstract Kaposi's sarcoma-associated virus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). KS is the most common AIDS-defining cancer in HIV-positive individuals, although KS can also occur in HIV-negative individuals. KS is a highly angiogenic tumor that is driven by KSHV-infected endothelial-derived spindle cells, and KS lesions express high levels of cytokines and angiogenic growth factors. We have found that KSHV infection significantly alters angiogenesis, migration, and survival of endothelial cells. We have found that KSHV viral proteins upregulate cytokines and chemokines and hypothesize that the upregulated cytokines and chemokines play important roles in driving angiogenesis and cell proliferation of KSHV-infected cells. Additionally, other cellular factors that are activated upon KSHV infection of endothelial cells will be explored for their role in angiogenesis and the KSHV lifecycle. In this application, we propose to determine how cellular and viral proteins promote endothelial cell migration, angiogenesis and survival of the infected cell and how this shapes the tumor microenvironment. We hypothesize that the modulation of cell migration, angiogenesis, survival and the tumor microenvironment by KSHV promotes oncogenesis and contributes to the pathogenesis associated with KSHV infection. Thus, the proposed studies will provide significant and biologically relevant insights into KSHV biology, and will also identify new targets for therapies against KSHV-associated cancers.