This is the renewal application for RO1 CA109232 Regulation of the KSHV LANA promoter. It responds to PA PA-07-455 Research on Malignancies in the Context of HIV/AIDS Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) is convincingly associated with Kaposi's Sarcoma (KS), an endothelial cell tumor and B-cell lymphoproliferative disease such as PEL in AIDS patients. During latency in KS and B-cell tumors fewer than 5% of KSHV genes are transcribed and these genes are implicated in KSHV episome maintenance and oncogenesis. Our prior real-time QPCR array analysis showed that every KS tumor expressed the viral latent genes and viral microRNAs. In addition a variable fraction also expressed viral lytic genes. Hence the question emerges what regulates KSHV latent genes? Our preliminary data suggest that understanding the latent/lytic switch in KSHV will have a significant impact on KS diagnosis and might uncover novel therapeutic targets to cure latent virus infection. Our new transgenic mouse data demonstrate that this ~1000bp sequence mediated B-cell specific activity of LANAp. We propose to continue our analysis of LANAp, expand the initial grant to in vivo analysis of the B-cell specificity of LANAp, the phenotypic characterization of LANA and KSHV miRNA expression in vivo and the analysis of cellular and viral factors in B cells and appropriate endothelial cell models.

Public Health Relevance

This is the renewal application to continue our work on understanding the principal latent regulatory unit of Kaposi sarcoma associated herpesvirus (KSHV). KSHV causes cancers in the context of HIV/AIDS and this regulatory unit directs the expression of essential viral genes, of which many exhibit oncogenic properties. Understanding their regulation will help unravel the biology of cancers caused by KSHV and, we hope, provide novel targets for intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109232-10
Application #
8657824
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2004-08-01
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
10
Fiscal Year
2014
Total Cost
$227,369
Indirect Cost
$73,741
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
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West, John A; Wicks, Megan; Gregory, Sean M et al. (2014) An important role for mitochondrial antiviral signaling protein in the Kaposi's sarcoma-associated herpesvirus life cycle. J Virol 88:5778-87
Chugh, Pauline E; Damania, Blossom A; Dittmer, Dirk P (2014) Toll-like receptor-3 is dispensable for the innate microRNA response to West Nile virus (WNV). PLoS One 9:e104770
Sin, Sang-Hoon; Kim, Yong Baek; Dittmer, Dirk P (2013) Latency locus complements MicroRNA 155 deficiency in vivo. J Virol 87:11908-11
Chugh, Pauline E; Sin, Sang-Hoon; Ozgur, Sezgin et al. (2013) Systemically circulating viral and tumor-derived microRNAs in KSHV-associated malignancies. PLoS Pathog 9:e1003484
Sin, Sang-Hoon; Dittmer, Dirk P (2013) Viral latency locus augments B-cell response in vivo to induce chronic marginal zone enlargement, plasma cell hyperplasia, and lymphoma. Blood 121:2952-63
Hilton, Isaac B; Simon, Jeremy M; Lieb, Jason D et al. (2013) The open chromatin landscape of Kaposi's sarcoma-associated herpesvirus. J Virol 87:11831-42
Dittmer, Dirk P (2011) Restricted Kaposi's sarcoma (KS) herpesvirus transcription in KS lesions from patients on successful antiretroviral therapy. MBio 2:e00138-11
Chen, Wuguo; Dittmer, Dirk P (2011) Ribosomal protein S6 interacts with the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus. J Virol 85:9495-505
Chen, Wuguo; Hilton, Isaac B; Staudt, Michelle R et al. (2010) Distinct p53, p53:LANA, and LANA complexes in Kaposi's Sarcoma--associated Herpesvirus Lymphomas. J Virol 84:3898-908

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