Latent and Lytic KSHV Infection Require Host Cell Metabolism

Thesis (Ph.D.)--University of Washington, 2016-06

Viruses are obligate intracellular parasites that depend on host cell machinery for their production and spread. Host metabolism is dramatically altered by several viruses to provide metabolic intermediates for biosynthetic as well as bioenergetic precursors. Understanding how a virus establishes and depends on a specific metabolic signature is critical to revealing possible therapeutic targets of infected cells. In this thesis, I further examined metabolic alterations during infection with the oncogenic virus, Kaposi’s Sarcoma Associated Herpesvirus (KSHV). Like all herpesviruses, KSHV has both a latent and lytic viral life stage. Both latent and lytic cells are found in the KS tumor, therefore, I identified the metabolic alterations in both latent and lytic cells. Previous research indicated that glycolysis and fatty acid synthesis (FAS) were required during latent KSHV infection for the survival of latently infected endothelial cells. In Chapter 1, I confirmed the requirement for FAS during latent infection. After presenting the background (Chapter 1) and Methods (Chapter 2), in Chapter 3, I defined the critical role glutamine metabolism plays in endothelial cells infected with KSHV. I also identify the cellular mechanism by which glutamine addiction is established during latency. Finally, in Chapter 4, I demonstrated that glycolysis, glutamine metabolism, and FAS are all required for maximal infectious KSHV virion production in lytically replicating cells. We show that each of these metabolic pathways contribute to virus production at a different step in lytic replication. Therefore, this body of work provides evidence that both latent and lytic KSHV infection depend on central carbon metabolism. These data may support the development or improvement of clinical therapies that target these carbon utilization pathways, thereby treating all infected cells of the KS tumor.