Integration site selection by HIV-1 and HIV-1 based vectors

描述(由申请人提供)：整合是艾滋病毒-1生命周期的一个重要步骤。遗憾的是，对整合地点选择的过程还没有完全了解。这项建议 重点是通过HIV-1和基于HIV-1的载体进行整合位点选择，这是逆转录病毒载体的一种主要类型。我们的目标是1)了解靶向的机制，2)开发可用于将这些载体靶向预定的染色体区域的方法，从而减少与癌基因附近整合相关的不良影响的可能性。我们将通过追求以下特定目标来实现我们的目标：1/我们将测试整合前复合体相关细胞蛋白HDAC4影响整合位点选择的假设；2/我们将测试以下假设，即整合酶结合细胞蛋白LEDGF/p75的染色质结合结构域可被利用来将HIV-1载体靶向预定的无基因染色体区域，以及靶向HDAC4的小分子化合物可用于控制整合位点选择。

DESCRIPTION (provided by applicant): 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.