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.
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.
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