Regulation of lymphangiogenesis by KSHV vIRF3

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Project Summary Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent for Kaposi's sarcoma (KS): especially, oral KS is one of the most common HIV-associated neoplasms. A number of studies have indicated that lymphangiogenic pathways are directly involved in KSHV malignancy. Thus, the proposed study is directed toward investigating how KSHV regulates the lymphangiogenic pathway, which may ultimately be used to design a targeted therapeutic strategy to block KSHV-induced malignancy. Based on our findings, we hypothesize that the KSHV vIRF3 latent protein directs HDAC5 angiogenic factor to induce the global gene expression change and hyper-sprouting formation for virus-induced lymphangiogenesis, which is a potential target for therapeutic strategy. In this proposal, we will study how the vIRF3 interaction blocks the phosphorylation-induced nuclear export of HDAC5; why vIRF3 functions are apparent only in LECs but not in BECs; and whether loss of the vIRF3 function affects KSHV oncogenesis in cultures. This proposal is targeted to enhance our understanding how KSHV deregulates lymphangiogenic pathway and thus should inform therapeutic strategies to block KSHV-induced malignancy, specifically oral KS.