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 #
3P01DE021954-03S1
Application #
8705634
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
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$234,324
Indirect Cost
$72,647
Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98105
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Fontaine, Krystal A; Camarda, Roman; Lagunoff, Michael (2014) Vaccinia virus requires glutamine but not glucose for efficient replication. J Virol 88:4366-74
Garrigues, H Jacques; Rubinchikova, Yelena E; Rose, Timothy M (2014) KSHV cell attachment sites revealed by ultra sensitive tyramide signal amplification (TSA) localize to membrane microdomains that are up-regulated on mitotic cells. Virology 452-453:75-85
Gutierrez, Kimberley D; Morris, Valerie A; Wu, David et al. (2013) Ets-1 is required for the activation of VEGFR3 during latent Kaposi's sarcoma-associated herpesvirus infection of endothelial cells. J Virol 87:6758-68
Morris, Valerie A; Punjabi, Almira S; Wells, Robert C et al. (2012) The KSHV viral IL-6 homolog is sufficient to induce blood to lymphatic endothelial cell differentiation. Virology 428:112-20
DiMaio, Terri A; Gutierrez, Kimberley D; Lagunoff, Michael (2011) Latent KSHV infection of endothelial cells induces integrin beta3 to activate angiogenic phenotypes. PLoS Pathog 7:e1002424