Global Metabolic Profiling of Infection by an Oncogenic Virus: KSHV Alters Endothelial Cell Fatty Acid Metabolism for the Survival of Latent Infection

Kaposi's Sarcoma-associated herpesvirus (KSHV) is an oncogenic virus and the etiologic agent of Kaposi’s Sarcoma (KS), the most common tumor of AIDS patients.  We analyzed global metabolic changes induced by latent infection with KSHV. Approximately one-third of the nearly 200 measured metabolites were altered following KSHV infection of endothelial cells, including metabolites of cellular pathways commonly regulated by cancer cells, including fatty acid synthesis (FAS). Interestingly, over half of the detectable long chain fatty acids (LCFAs) detected in our screen were significantly increased by KSHV infection. We have now shown that KSHV infection leads to the elevation of metabolites involved in FAS and lipid droplet formation in infected cells.  FAS is required for the survival of infected endothelial cells, and if inhibited leads to apoptosis.  Additionally, our metabolomics data show that all essential fatty acids (EFAs) detected were elevated during KSHV infection. EFAs are LCFAs that mammalian cells are incapable of synthesizing, and must be actively taken up from the extracellular environment. I hypothesize that KSHV induction of EFA uptake is required for viral persistence and survival of infected cells. Work is currently being done to determine both cellular and viral mechanisms of EFA uptake during infection and identify if EFA uptake is required for host cell survival and viral persistence. This work will provide key information regarding the metabolic requirements for long-term survival of cells infected with KSHV. Our study provides insight as to how oncogenic viruses can induce metabolic alterations, many of which are common to cancer cells.