Grant: Operating Grant - PA: HIV/AIDS Bridge Funding - Biomedical/Clinical Stream

The establishment of HIV infection requires the integration of viral cDNA into host genome. To achieve this, HIV cDNA must be transported from cytoplasm to the nucleus, and targeted to host chromatin. HIV-1 integrase is an enzymatic protein that catalyzes viral DNA integration. In addition, this viral protein plays important roles in HIV nuclear import and chromatin targeting. Due to its essential roles in the early stage of HIV infection, extensive research has been focused to understand how IN contributes to HIV replication. However, the mechanism underlying its actions is still not fully understood. We have focused our effort to understand how integrase functions during HIV replication, and recently we demonstrated that HIV integrase is able to interact with two new cellular proteins, one is a nuclear import factor which is highly expressed during cell differentiation, and another is involved for both DNA binding and repair. Interestingly, the deletion of these proteins in CD4+ T cells significantly impaired HIV replication. All of these results suggest that binding of HIV integrase to these cellular factors may significantly contribute to HIV nuclear import, chromatin targeting and the integration. In this proposed, we will continue our studies to further investigate the molecular mechanism underlying these HIV/host protein interactions and to elucidate where and how they play important roles during HIV replication. The optimal goal of these studies is not only to gain better understanding of how HIV IN hijacks cellular machinery for efficient HIV replication, but also to provide a proof-of-concept for these HIV/host interactions as novel targets for the development of new strategies to block HIV infection before its integration.