Kaposi's sarcoma-associated virus (KSHV) is thought to be an etiological agent of Kaposi's sarcoma (KS) tumors and pleural effusion lymphoma (PEL). The proposed research is directed toward investigating the molecular mechanism of deregulation of cell growth control induced by the KSHV K1 gene product. As seen with growth deregulating proteins of other gamma herpesviruses, K1 has pleotropic effects on cellular signal transduction and proliferation. Our preliminary studies have found that KSHV K1 is able to elicit a cellular signal transduction cascade through its carboxyl immunoreceptor tyrosine-based activation motif (ITAM), that its expression induces lymphoma in transgenic mice, and that K1 is capable of substituting for the herpesvirus saimiri (HVS) STP oncogene in immortalization of primary lymphocytes in culture and in lymphoma induction in primates. Based on our preliminary results, we hypothesize that the ITAM-mediated signal transduction of K1 contributes to the development of KSHV pathogenesis. Our biochemical and immunological studies will define in greater detail the mechanisms used by K1 to elicit cellular signal transduction and proliferation. To define the role of K1 in viral pathogenesis in vivo, we will test whether K1 expression in B and/or endothelial cells in transgenic mice results in the disease induction, and whether wt K1 and its mutants in the context of HVS are capable of contributing to the development of lymphoma in non-natural host common marmosets and the persistent infection in natural host squirrel monkeys. Because of the lack of cell culture systems and animal models for KSHV, these approaches provide a unique opportunity to investigate the contribution of the K1 gene to the KSHV pathogenesis. The proposed studies will provide an understanding of novel pathogenic strategies of KSHV to deregulate cell growth control and contribute to virus-induced pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA106156-03
Application #
7090692
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2004-07-16
Project End
2009-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
3
Fiscal Year
2006
Total Cost
$304,477
Indirect Cost
Name
Harvard University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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