Opportunistic infections are a major cause of morbidity and mortality of AIDS patients in developing countries and AIDS patients are susceptible to a number of cancers caused by opportunistic infections. Kaposi's Sarcoma (KS) is the most common tumor of AIDS patients and is the most commonly reported tumor overall in parts of Africa. The etiologic agent of KS is Kaposi's Sarcoma-associated herpesvirus (KSHV or HHV-8). KSHV is invariably found in the main KS tumor cell, the spindle cell, a cell of endothelial origin and is predominantly found in th latent state. There are no drugs to target latent infection of herpesviruses. Therefore, an important therapeutic approach is to delineate and target host endothelial cell processes required for KSHV latency. Recent studies have shown that pathologic changes in cell metabolism can be a driver of oncogenesis rather than simply an adaptation to the tumor environment. While a few studies have examined alterations of cellular metabolism during lytic infection of viruses, we were the first to examine changes in cellular metabolism during latent infection. We demonstrated that latent KSHV infection of endothelial cells leads to an alteration in glucose carbon utilization, specifically inducing aerobic glycolysis. Importantly, we found that KSHV induction of aerobic glycolysis is essential for the survival of latently infected cells. Our preliminary data for this proposal show that latent KSHV infection also induces glutamine uptake and requires glutamine for the survival of latently infected cells. Therefore, altered utilization f both glucose and glutamine, are critical for the maintenance of KSHV latency. In this proposal, we will examine how glucose and glutamine are utilized specifically in endothelial cells latently infected with KSHV, the relevant cell type for KS tumors. In the first aim we will analyze glucose metabolism during latent infection to further identify how glucose carbons are metabolized and why these alterations are needed for the survival of latent infection. We will also examine the cellular and viral mechanisms for induction of altered glucose utilization. In the second aim we will analyze the cellular and viral mechanism of increased glutamine uptake and determine how glutamine is metabolized during latent infection. Our data indicate that pathologic changes in cellular metabolism induced by KSHV could provide novel therapeutic targets for latently infected cells and would ultimately provide therapeutic targets for KS tumors in AIDS patients.

Public Health Relevance

Kaposi's Sarcoma is the most common tumor of AIDS patients worldwide and is caused by the Kaposi's Sarcoma-associated herpesvirus. All current drugs for herpes viruses target lytic infection; however, in the KS tumor the virus is predominantly latent. We have identified virus induced pathologic changes in the utilization of cellular metabolism that are essential for the survival of latently infected cells and can be used to target latently infected cells and thereby target KS tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA189986-05
Application #
9605007
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2014-12-16
Project End
2020-03-31
Budget Start
2018-12-01
Budget End
2020-03-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Bruce, A Gregory; Barcy, Serge; DiMaio, Terri et al. (2017) Quantitative Analysis of the KSHV Transcriptome Following Primary Infection of Blood and Lymphatic Endothelial Cells. Pathogens 6:
Sychev, Zoi E; Hu, Alex; DiMaio, Terri A et al. (2017) Integrated systems biology analysis of KSHV latent infection reveals viral induction and reliance on peroxisome mediated lipid metabolism. PLoS Pathog 13:e1006256
Sanchez, Erica L; Pulliam, Thomas H; Dimaio, Terri A et al. (2017) Glycolysis, Glutaminolysis, and Fatty Acid Synthesis Are Required for Distinct Stages of Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication. J Virol 91:
DiMaio, Terri A; Wentz, Breanna L; Lagunoff, Michael (2016) Isolation and characterization of circulating lymphatic endothelial colony forming cells. Exp Cell Res 340:159-69
Lagunoff, Michael (2016) Activation of cellular metabolism during latent Kaposi's Sarcoma herpesvirus infection. Curr Opin Virol 19:45-9
Sanchez, Erica L; Carroll, Patrick A; Thalhofer, Angel B et al. (2015) Latent KSHV Infected Endothelial Cells Are Glutamine Addicted and Require Glutaminolysis for Survival. PLoS Pathog 11:e1005052
Sanchez, Erica L; Lagunoff, Michael (2015) Viral activation of cellular metabolism. Virology 479-480:609-18