KSHV alteration of cellular metabolism

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Kaposi's Sarcoma (KS) is the most common tumor of AIDS patients worldwide and is the most commonly reported tumor in parts of Africa. The predominant tumor cell is the spindle cell, a cell of endothelial origin. The etiologic agent of KS is the Kaposi's Sarcoma-associated herpesvirus (KSHV or HHV-8), a gamma herpesvirus. KSHV is latent in greater than 95% of the spindle cells in the tumor, with a low percentage of spindle cells supporting lytic replication. Infection of endothelial cells in culture leads to similar percentages of latent and lytic infection leading us to use cultured endothelial cell infection as a model of infection. We have demonstrated that KSHV dramatically alters endothelial cell metabolism upon infection including induction of glycolysis, glutaminolysis and fatty acid synthesis. Interestingly, all of these metabolic pathways are also induced in tumor cells from a variety of cancers and are required for the survival of cancer cells. Inhibition of these pathways induces cell death in latently infected cells but not mock infected cells indicating that this is a potential therapeutic target for intervention. These pathways center around the mitochondria. In preliminary data we found that mitochondrial translation is necessary for proliferation and survival of latently infected cells. In this proposal we will determine the role of the mitochondria in KSHV latency and how KSHV directly alters the mitochondria leading to altered mitochondrial function. We will also examine how KSHV alteration of mitochondria alters other metabolic pathways in the latently infected cells. These studies will shed light on how KSHV latent infection of endothelial cells requires alterations in cellular metabolism for survival through determination of how KSHV alters cellular stress and mitochondria as well as the viral mechanisms involved. A number of the mitochondrial pathway examined in this proposal are therapeutic targets with FDA approved drugs and could potentially be used to target KSHV latent infection and ultimately KS tumors. !