Glycolysis, Glutaminolysis, and Fatty Acid Synthesis Are Required for Distinct Stages of Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS). KSHV infection induces and requires multiple metabolic pathways, including the glycolysis, glutaminolysis, and fatty acid synthesis (FAS) pathways, for the survival of latently infected endothelial cells. To determine the metabolic requirements for productive KSHV infection, we induced lytic replication in the presence of inhibitors of different metabolic pathways. We found that glycolysis, glutaminolysis, and FAS are all required for maximal KSHV virus production and that these pathways appear to participate in virus production at different stages of the viral life cycle. Glycolysis and glutaminolysis, but not FAS, inhibit viral genome replication and, interestingly, are required for different early steps of lytic gene expression. Glycolysis is necessary for early gene transcription, while glutaminolysis is necessary for early gene translation but not transcription. Inhibition of FAS resulted in decreased production of extracellular virions but did not reduce intracellular genome levels or block intracellular virion production. However, in the presence of FAS inhibitors, the intracellular virions are noninfectious, indicating that FAS is required for virion assembly or maturation. KS tumors support both latent and lytic KSHV replication. Previous work has shown that multiple cellular metabolic pathways are required for latency, and we now show that these metabolic pathways are required for efficient lytic replication, providing novel therapeutic avenues for KS tumors. KSHV is the etiologic agent of Kaposi's sarcoma, the most common tumor of AIDS patients. KS spindle cells, the main tumor cells, all contain KSHV, mostly in the latent state, during which there is limited viral gene expression. However, a percentage of spindle cells support lytic replication and production of virus and these cells are thought to contribute to overall tumor formation. Our previous findings showed that latently infected cells are sensitive to inhibitors of cellular metabolic pathways, including glycolysis, glutaminolysis, and fatty acid synthesis. Here we found that these same inhibitors block the production of infectious virus from lytically infected cells, each at a different stage of viral replication. Therefore, inhibition of specific cellular metabolic pathways can both eliminate latently infected cells and block lytic replication, thereby inhibiting infection of new cells. Inhibition of metabolic pathways provides novel therapeutic approaches for KS tumors.

HACE1, an E3 Ubiquitin Protein Ligase, Mitigates Kaposi’s Sarcoma-Associated Herpesvirus Infection-Induced Oxidative Stress by Promoting Nrf2 Activity

“…Glutamine is required by many cancer cells for their survival. Studies demonstrate that KSHV has evolved to exploit the cellular metabolism for its survival and maintenance of latently infected cells and to require glutamine for anabolic proliferation of KSHV-transformed cells (64,65) and maintenance of endothelial cells latently infected with KSHV (42). Loss of HACE1 has been linked with ROS-dependent increased glutamine uptake in mouse embryonic fibroblasts (43).…”

Avian reovirus σA-modulated suppression of lactate dehydrogenase and upregulation of glutaminolysis and the mTOC1/eIF4E/HIF-1α pathway to enhance glycolysis and the TCA cycle for virus replication

“…α-KG is a key intermediate in the TCA cycle and can be produced from oxidative decarboxylation of isocitrate by IDH and oxidative deamination of glutamate by GDH in glutaminolysis (Plaitakis, Kalef-Ezra, Kotzamani, Zaganas, & Spanaki, 2017). Some viruses have been reported to influence glutaminolysis (Chambers, Maguire, & Alwine, 2010;Sanchez et al, 2017), so it is interesting to know whether ARV also requires glutaminolysis for its propagation. As demonstrated in Figure 8a, HIF-1α in cells treated with BPTES, an inhibitor of glutaminase, was significantly decreased compared with σA-transfected cells.…”

Host Src controls gallid alpha herpesvirus 1 intercellular spread in a cellular fatty acid metabolism-dependent manner

“…Considering the rapid establishment of latent infection during the initial infection with ILTV, the opposite effects of Src activation by ILTV infection most likely reflect a strategy that evolves during the co-evolution of ILTV and its host, which establishes a balance for the pathogen-host interaction. Host metabolic requirements for maximal viral production have been examined in several human herpesviruses, including human cytomegalovirus (HCMV), herpes simplex virus 1 (HSV-1), and KSHV (Delgado et al, 2012;Munger et al, 2006Munger et al, , 2008Sanchez et al, 2017;Vastag et al, 2011), and the results suggest that inhibition of specific cellular metabolic pathways can both eliminate latently infected cells and block lytic replication, thus providing opportunities for the development of novel therapeutic approaches for herpesviruses. Although similarities exist, significant differences in the utilization of host metabolic resources by these herpesviruses have been reported.…”

“…Many viruses have been shown to induce fatty acid synthesis in host cells, which provides a stable carbon source and sufficient energy for viral replication, viral spread and even the prolonged survival of infected cells (Rodríguez-Sánchez and Munger, 2019;Sanchez and Lagunoff, 2015;Sanchez et al, 2017). Although the mechanism remains unclear for ILTV, the utilization of host fatty acid metabolism has been found to be important for both latent and lytic infections with human gamma herpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV), and the survival of infected cells (Delgado et al, 2012;Sanchez et al, 2017). Thus, a better understanding of the involvement of fatty acid metabolism in viral infection may lead to the development of novel therapeutic approaches targeting specific cellular metabolic processes.…”