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 #
5P01DE021954-03
Application #
8463813
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
$1,335,154
Indirect Cost
$537,605
Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98105
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
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; Lagunoff, Michael (2015) Viral activation of cellular metabolism. Virology 479-480:609-18
Fontaine, Krystal A; Sanchez, Erica L; Camarda, Roman et al. (2015) Dengue virus induces and requires glycolysis for optimal replication. J Virol 89:2358-66
Bruce, A Gregory; Thouless, Margaret E; Haines, Anthony S et al. (2015) Complete genome sequence of Pig-tailed macaque rhadinovirus 2 and its evolutionary relationship with rhesus macaque rhadinovirus and human herpesvirus 8/Kaposi's sarcoma-associated herpesvirus. J Virol 89:3888-909
DiMaio, Terri A; Gutierrez, Kimberley D; Lagunoff, Michael (2014) Kaposi's sarcoma-associated herpesvirus downregulates transforming growth factor β2 to promote enhanced stability of capillary-like tube formation. J Virol 88:14301-9
Fontaine, Krystal A; Camarda, Roman; Lagunoff, Michael (2014) Vaccinia virus requires glutamine but not glucose for efficient replication. J Virol 88:4366-74
Staheli, Jeannette P; Dyen, Michael R; Lewis, Patrick et al. (2014) Discovery and biological characterization of two novel pig-tailed macaque homologs of HHV-6 and HHV-7. Virology 471-473:126-40
Stockinger, Diane E; Fong, Derek L; Vogel, Keith W et al. (2014) Oral squamous cell carcinoma in a pigtailed macaque (Macaca nemestrina). Comp Med 64:234-9

Showing the most recent 10 out of 23 publications