Many metabolic pathways are dramatically altered in cancer cells. These alterations are thought to provide cancer cells with the necessary energy and substrates for rapid cell division. Otto Warburg first demonstrated that most cancer cells have increased levels of glycolysis, even in the presence of oxygen, indicating that cancer cells dramatically alter their metabolism 
. The increased aerobic glycolysis seen in most cancer cells, now termed the Warburg effect, is often accompanied by decreased oxygen usage, indicating a dramatic shift in the source of energy for tumor cells. Cancer cells become dependent on increased glycolysis and thus require increased glucose uptake for survival 
. In addition to the Warburg effect, many other metabolic changes occur in most tumor cells, including increases in lipogenesis, amino acid metabolism, and the pentose phosphate pathway among others.
Recently, global changes in cellular metabolism have been studied using metabolomic approaches 
. Metabolomics generally involves the use of gas chromatography-mass spectrometry (GC-MS) and/or Liquid chromatography–mass spectrometry (LC-MS) to simultaneously detect changes in a wide variety of metabolites 
. Metabolomic approaches have allowed for the determination of global alterations of metabolism in tumor cells as well as in virally infected cells.
As non-living entities, viruses do not inherently have their own metabolism. However, upon infection, viruses dramatically alter the metabolism of the host cell. Viral alteration of host cell metabolism can provide the substrates necessary for viral replication. For example, alteration of host cell metabolism can provide the increased nucleotides necessary for genome replication or increased free amino acids needed for rapid viral protein synthesis. Virally-induced alterations of host metabolic pathways are likely to also be important for viral pathogenesis. Viral metabolomic studies were first used to identify changes in host cellular metabolism induced by human cytomegalovirus (HCMV) lytic infection 
. These studies found that HCMV infection leads to the alteration of many key metabolic pathways including changes that are essential for lytic replication. Subsequently, changes in the cellular metabolic profile were determined for cells infected by other viruses, including hepatitis C virus (HCV), human immunodeficiency virus (HIV) and herpes simplex virus (HSV) 
. These studies identified numerous metabolic alterations in infected cells. However, metabolomic studies have yet to be done on viruses that directly induce oncogenesis.
Kaposi's Sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's Sarcoma (KS). KS is the most common tumor in parts of central Africa as well as in AIDS patients worldwide. KS lesions are predominantly populated by spindle cells of endothelial origin 
. At late stages, all spindle cells in the tumor are infected with KSHV 
. Like all herpesviruses, KSHV has both lytic and latent viral phases. During lytic replication, there is broad viral gene expression and the virus is rapidly replicated, ultimately leading to cell death. During latency, viral gene expression is limited, supporting expression of genes necessary for the maintenance of the latent episome and for infected cell survival. In KS spindle cells, KSHV is predominantly in the latent state, however, a few percent of the cells express viral markers of lytic replication 
. KSHV infection of cultured endothelial cells yields similar levels of latent and lytic infection 
Our previous studies found that KSHV infection of cultured endothelial cells directly induces the Warburg effect 
. KSHV infection of endothelial cells leads to increased glucose uptake as well as increased lactic acid production. Expression of the glucose transporter, GLUT3, and the first rate-limiting enzyme in glycolysis, hexokinase-2, were also increased following latent infection. KSHV infection of endothelial cells also leads to significant decreases in oxygen consumption. Interestingly, both inhibition of lactate dehydrogenase, an essential enzyme for the conversion of pyruvate to lactate, or inhibition of glucose processing by a non-hydrolysable glucose analog, led to increased death of cells latently infected with KSHV 
. These results indicate that glycolysis is required for the survival of cells latently infected with KSHV. This was the first evidence that KSHV directly induces a metabolic alteration common to most cancer cells. Furthermore, as observed in many cancer cells, this alteration is required for the survival of infected cells.
To determine if KSHV induces other metabolic changes similar to cancer cells, we performed a global screen to detect metabolites in mock- and KSHV-infected cells at 48 and 96 hours post infection (hpi). At 48 and 96 hpi, greater than 90% of the cells expressed a latent marker of infection, while only 1–5% of the cells expressed a marker of lytic replication. By 48 hpi, KSHV altered greater than one-quarter of the approximately 200 detectable metabolites and nearly one-third were altered by 96 hpi. Metabolites of several pathways commonly dysregulated in tumor cells were altered by KSHV, including glycolysis, amino acid metabolism, the pentose phosphate pathway and lipogenesis. KSHV infection leads to elevated levels of over half of the detectable metabolite products of de novo
fatty acid synthesis (FAS or lipogenesis), and was concurrent with increased lipid droplets in latently infected endothelial cells. Lipid droplets are lipid-rich cytoplasmic organelles (diameter <1–100 µm) that store cellular energy in the form of triacylglycerols and also store phospholipids and sterols, the building blocks of membranes 
. Therefore, lipid droplets provide both readily accessible energy as well as cellular membrane material.
Fatty acids are essential substrates for energy metabolism and are the major components of all biological lipid membranes 
. Animal fatty acids can be derived exogenously from diet or endogenously by de novo
lipogenesis. Normal cells predominantly acquire fatty acids from dietary sources rather than de novo
lipogenesis. However, the majority of fatty acids from cancer cells are derived by de novo
lipogenesis even when exogenous fatty acids are available 
. Induced lipogenesis is thought to aid in rapid cell division by generating the raw material needed for membrane production and the required metabolites for cell proliferation. Previous studies have shown that increased lipogenesis is required for the survival of many cancer cells 
. We show here that the induction of FAS is also required for the survival of endothelial cells latently infected with KSHV. Inhibitors of FAS led to greatly increased apoptotic death of latently infected cells, as compared to their mock-infected counterparts. This effect was reversed by the addition of palmitc acid, the first fatty acid metabolite that is produced downstream of the drugs we used to block FAS. Therefore, the products of FAS are necessary for the survival of endothelial cells latently infected with KSHV. Inhibition of fatty acid synthesis provides a potential therapeutic target for KSHV and ultimately KS tumors.