This is a new Program Project to establish an interdisciplinary research program to determine the role of the oropharyngeal environment in the transmission and pathogenesis of the Kaposi's sarcoma-associated herpesvirus (KSHV). Kaposi's sarcoma (KS) was recognized as one of the first clinical manifestations of HIV, and today remains the most common AIDS-associated malignancy. KSHV is endemic in Sub-Saharan Africa, with extremely high infection rates in children, adolescents and adults. Compounded with the high rate of HIV and AIDS in this geographical area, pediatric and adult KS are some of the most common malignancies, with the highest fatality rates. The Project leaders have played key roles in the initial discovery and characterization of KSHV, and in the role of the oral environment in the acquisition and transmission of the virus. Furthermore, they have also been at the forefront of research on the role of the immune response in regulating KSHV infection. Four interrelated research projects with associated administrative, cell culture and clinical cores are proposed. These projects collectively address fundamental questions regarding how KSHV infection leads to KS. Project 1(PI,T. Rose) will study the role of cell-cell transmission of KSHV during acquisition in oral tissues and dissemination to peripheral tissues. Project 2 (PI, J. Vieira) will investigate the reactivation of latently-infected cells to begin producing infectious virus. Project 3 (PI. M. LagunofO will examine the process by which KSHV infection of cells causes them to differentiate into KS tumor cells. Project 4 (Co-Pls, S. Gantt/S. Barcy) seeks to identify which immune responses are responsible for controlling KSHV infection, and how HIV impairs these responses. Finally, each of these Projects will explore the clinical relevance of their findings in natural human KSHV infection, by collaborating with the Uganda Program on Cancer and Infectious Disease (UPCID) to study infection in communities with the highest known incidence of KS. The interrelated nature of these four projects, the technological synergism and the existing research collaborations provide an exceptionally strong basis for this project, which could lead to new therapeutic treatments for KSHV infection and KS.

Public Health Relevance

The Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is the cause of KS and two other AIDS-related malignancies. KS is the most common oral tumor associated with HIV/AIDS and is one of the most common pediatric and adult tumors in Sub-Saharan Africa. This project will investigate the immune control, activation, transmission and pathogenesis of KSHV in order to develop effective vaccines and therapeutics for this devastating viral pathogen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Program Projects (P01)
Project #
1P01DE021954-01
Application #
8130341
Study Section
Special Emphasis Panel (ZDE1-MH (03))
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
2011-06-07
Project End
2016-04-30
Budget Start
2011-06-07
Budget End
2012-04-30
Support Year
1
Fiscal Year
2011
Total Cost
$1,507,828
Indirect Cost
Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98105
Ikoma, Minako; Gantt, Soren; Casper, Corey et al. (2018) KSHV oral shedding and plasma viremia result in significant changes in the extracellular tumorigenic miRNA expression profile in individuals infected with the malaria parasite. PLoS One 13:e0192659
Garrigues, H Jacques; Howard, Kellie; Barcy, Serge et al. (2017) Full-Length Isoforms of Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen Accumulate in the Cytoplasm of Cells Undergoing the Lytic Cycle of Replication. J Virol 91:
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
Bruce, A Gregory; Horst, Jeremy A; Rose, Timothy M (2016) Conservation of the glycoprotein B homologs of the Kaposi?s sarcoma-associated herpesvirus (KSHV/HHV8) and old world primate rhadinoviruses of chimpanzees and macaques. Virology 494:29-46
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

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