Kaposi's sarcoma (KS) remains the most common tumor arising in patients with HIV/AIDS, and involvement of the oral cavity represents one of the most common clinical manifestations of this tumor. Kaposi's sarcoma-associated herpesvirus (KSHV) replication and ongoing infection of target cells plays an important role in KS pathogenesis. An amino acid membrane transport protein subunit, xCT, maintains intracellular glutathione stores to enhance the survival of cells producing reactive nitrogen species (RNS), and xCT was recently identified as a fusion-entry receptor for KSHV (Kaleeba and Berger, Science, 2006). A number of intracellular and extracellular triggers regulate xCT expression, including binding of the xCT promoter by transcription regulators and the activation of positive transcription regulators by RNS. We have determined recently that xCT is expressed by multiple cell types within KS lesions and circulating mononuclear cells from HIV-infected patients, with cells from KSHV/HIV co-infected patients exhibiting the highest xCT expression. However, it is unknown whether KSHV itself regulates xCT expression to promote KSHV infection and persistence in the local environment. KSHV infects macrophages within KS lesions, and macrophages are a principal source of RNS. Using a novel macrophage cell culture system, our preliminary data suggest that KSHV microRNA suppress BACH-1, a negative transcription regulator of xCT expression, and that KSHV induces RNS secretion by macrophages. Based on these preliminary data, we hypothesize that KSHV promotes its own persistence in the local environment by upregulating xCT expression through both paracrine and autocrine mechanisms, and that targeting xCT regulatory pathways reduces KSHV infection and persistence in the microenvironment. To address this hypothesis, we propose two independent aims: 1) to determine mechanisms and functional outcomes for xCT regulation by KSHV; and 2) to determine clinical relationships between KSHV infection, xCT expression and RNS production in HIV-infected patients at greatest risk for KS. Through these efforts, we hope to provide the framework for developing novel therapeutic strategies for KS through the targeting of xCT and the reduction of KSHV infection and persistence within the tumor microenvironment.