Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). KS is still the most common AIDS-defining cancer in HIV-positive individuals, although KS can also occur in HIV-negative individuals. In certain regions of sub-Saharan Africa, KS is the most prevalent cancer. Other immunosuppressed individuals such as transplant patients also develop KS much more frequently than the healthy population. During the previous funding period we had reported that KSHV and the K1 viral protein can activate the PI3K/Akt/mTOR pathway, upregulate angiogenic factors, and protect cells from apoptosis. Our overarching hypothesis is that KSHV viral proteins modulate pro-survival cellular signaling pathways that are also conducive to transformation. In this application, we propose to determine the mechanisms by which KSHV and its viral proteins modulate the PI3K signaling pathway at multiple nodes. Activation of the PI3K/Akt/mTOR signaling pathway is critical for survival of KSHV- infected cells as well as the survival of KS and PEL tumors. We propose to identify novel host factors that are critical for survival of KSHV-infected cells, which may also help identify new proteins involved in cell survival. Furthermore, our preliminary data suggest that KSHV alters cellular metabolic pathways including glycolysis and fatty acid synthesis. We propose to determine how KSHV and its viral proteins alter host cell metabolism to the advantage of the virus. The proposed studies will provide significant and biologically relevant insights into the functions of viral signaling proteins, and may yield a new target for anti-KSHV therapies.

Public Health Relevance

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). KS is still the most common AIDS-defining cancer in HIV-positive individuals. In certain regions of sub-Saharan Africa, KS is the most prevalent cancer. Other immunosuppressed individuals such as transplant patients also develop KS much more frequently than the healthy population. We had previously reported that KSHV and the K1 viral protein can activate the PI3K/Akt/mTOR pathway and protect cells from apoptosis. Our overarching hypothesis is that KSHV viral proteins modulate pro-survival cellular signaling pathways that are also conducive to transformation. Here, we propose to determine the mechanisms by which KSHV and its viral proteins modulate the PI3K signaling pathway. Activation of the PI3K/Akt/mTOR signaling pathway is critical for survival of KSHV- infected cells as well as the survival of KS and PEL tumors. We propose to identify novel host factors that are critical for survival of KSHV-infected cells. Furthermore, our preliminary data suggest that KSHV alters cellular metabolic pathways including glycolysis and fatty acid synthesis. We propose to determine how KSHV and its viral proteins alter host cell metabolism to the advantage of the virus. The proposed studies will provide significant and biologically relevant insights into the functions of viral signaling proteins, and may yield a new target for anti-KSHV therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA096500-11A1
Application #
8606968
Study Section
Special Emphasis Panel (ZRG1-AARR-K (03))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2002-07-01
Project End
2018-05-31
Budget Start
2013-08-01
Budget End
2014-05-31
Support Year
11
Fiscal Year
2013
Total Cost
$281,108
Indirect Cost
$94,584
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Anders, Penny; Bhende, Prasanna M; Foote, Michael et al. (2015) Dual inhibition of phosphatidylinositol 3-kinase/mammalian target of rapamycin and mitogen activated protein kinase pathways in non-Hodgkin lymphoma. Leuk Lymphoma 56:263-6
Giffin, Louise; Damania, Blossom (2014) KSHV: pathways to tumorigenesis and persistent infection. Adv Virus Res 88:111-59
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Giffin, Louise; Yan, Feng; Ben Major, M et al. (2014) Modulation of Kaposi's sarcoma-associated herpesvirus interleukin-6 function by hypoxia-upregulated protein 1. J Virol 88:9429-41
Dillon, Patrick J; Gregory, Sean M; Tamburro, Kristen et al. (2013) Tousled-like kinases modulate reactivation of gammaherpesviruses from latency. Cell Host Microbe 13:204-14
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Meckes Jr, David G; Gunawardena, Harsha P; Dekroon, Robert M et al. (2013) Modulation of B-cell exosome proteins by gamma herpesvirus infection. Proc Natl Acad Sci U S A 110:E2925-33
Dittmer, Dirk P; Bhatt, Aadra P; Damania, Blossom (2012) Rapalogs in viral cancers. Expert Opin Investig Drugs 21:135-8
Roy, Debasmita; Sin, Sang-Hoon; Damania, Blossom et al. (2011) Tumor suppressor genes FHIT and WWOX are deleted in primary effusion lymphoma (PEL) cell lines. Blood 118:e32-9

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