Integration is an essential step of the HIV-1 life-cycle. Unfortunately, the process of integration site selection is not yet fully understood. This proposal is focused on integration site selection by HIV-1 and HIV-1- based vectors, which are a major type of retroviral vectors. Our objectives are 1) to understand the mechanism of targeting, and 2) to develop methods that can be used to target these vectors to predetermined chromosomal regions, and thus reduce the likelihood of undesirable effects associated with integration in the vicinity of oncogenes. We will achieve our objectives by pursuing the following Specific Aims: 1/ We will test the hypothesis that the preintegration complex-associated cellular protein HDAC4 influences integration site selection;2/ We will test the hypotheses that the chromatin-binding domain of the integrase-binding cellular protein LEDGF/p75 can be exploited to target HIV-1-based vectors to predetermined, gene-free chromosomal regions and that small compounds targeting HDAC4 can be used to control integration site selection.
Experiments, which are proposed in this application, should significantly enhance our understanding of the role of cellular co-factors in integration site selection by retroviral vectors and HIV-1. In addition, our results will lead to novel therapeutic approaches that will decrease the danger of cancer development due to integration in undesirable regions of the human genome.