Kaposi's sarcoma-associated virus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). KS is a highly angiogenic tumor that is driven by KSHV-infected endothelial cells, and KS lesions express high levels of cytokines and angiogenic growth factors. We have found that latent KSHV infection dramatically alters angiogenesis, migration, and survival of endothelial cells. Latent KSHV infection of endothelial cells results in the upregulation of multiple cytokines and chemokines. We hypothesize that the upregulated cytokines and chemokines play important roles in driving angiogenesis and cell proliferation of KSHV-infected cells, and we propose to determine the mechanism by which these factors regulate cell growth, survival, and angiogenesis. We will also determine how KSHV infection affects cell migration. Finally, we have identified cellular and viral proteins that modulate the ubiquitin pathway. Hence, we propose to determine how these factors alter cellular ubiquitination pathways, to promote cell migration and survival of the infected cell. In summary, we propose to analyze the biological pathways that are altered upon KSHV infection of endothelial cells in order to understand the mechanism of KSHV-mediated oncogenesis. We hypothesize that the modulation of cell migration, angiogenesis and anti-apoptotic pathways by KSHV promotes tumorigenesis and contributes to the pathogenesis associated with KSHV infection. Thus, the proposed studies will provide significant and biologically relevant insights into KSHV biology, and will also identify new targets for future therapies against KSHV-associated cancers.

Public Health Relevance

KSHV is a human pathogen associated with three different human cancer. Hence it is important to understand how KSHV establishes life-long latency in its host and the mechanisms by which KSHV promotes tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA019014-32A1
Application #
8166055
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Project Start
1997-05-01
Project End
2016-06-30
Budget Start
2011-07-27
Budget End
2012-06-30
Support Year
32
Fiscal Year
2011
Total Cost
$291,379
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Host, Kurtis M; Horner, Marie-Josephe; van der Gronde, Toon et al. (2017) Kaposi's sarcoma in Malawi: a continued problem for HIV-positive and HIV-negative individuals. AIDS 31:318-319
Westmoreland, Katherine D; Montgomery, Nathan D; Stanley, Christopher C et al. (2017) Plasma Epstein-Barr virus DNA for pediatric Burkitt lymphoma diagnosis, prognosis and response assessment in Malawi. Int J Cancer 140:2509-2516
Ma, Zhe; Hopcraft, Sharon E; Yang, Fan et al. (2017) NLRX1 negatively modulates type I IFN to facilitate KSHV reactivation from latency. PLoS Pathog 13:e1006350
Dittmer, Dirk P; Krown, Susan E; Mitsuyasu, Ronald (2017) Exclusion of Kaposi Sarcoma From Analysis of Cancer Burden. JAMA Oncol 3:1429
Westmoreland, Katherine D; Stanley, Christopher C; Montgomery, Nathan D et al. (2017) Hodgkin lymphoma, HIV, and Epstein-Barr virus in Malawi: Longitudinal results from the Kamuzu Central Hospital Lymphoma study. Pediatr Blood Cancer 64:
Schifano, Jason M; Corcoran, Kathleen; Kelkar, Hemant et al. (2017) Expression of the Antisense-to-Latency Transcript Long Noncoding RNA in Kaposi's Sarcoma-Associated Herpesvirus. J Virol 91:
Lee, Jennifer S; Cole, Stephen R; Richardson, David B et al. (2017) Incomplete viral suppression and mortality in HIV patients after antiretroviral therapy initiation. AIDS 31:1989-1997
Bermek, Oya; Weller, Sandra K; Griffith, Jack D (2017) The UL8 subunit of the helicase-primase complex of herpes simplex virus promotes DNA annealing and has a high affinity for replication forks. J Biol Chem 292:15611-15621
Raab-Traub, Nancy; Dittmer, Dirk P (2017) Viral effects on the content and function of extracellular vesicles. Nat Rev Microbiol 15:559-572
Dyson, Ossie F; Pagano, Joseph S; Whitehurst, Christopher B (2017) The Translesion Polymerase Pol ? Is Required for Efficient Epstein-Barr Virus Infectivity and Is Regulated by the Viral Deubiquitinating Enzyme BPLF1. J Virol 91:

Showing the most recent 10 out of 303 publications