Characterization of Super Restriction Factors and Prediction of Host-HIV Interfaces

人类基因组已经进化出一系列具有靶向HIV的潜力的抗病毒基因。然而，在这方面， 这些抗病毒蛋白质的效力在进化方面动态波动;病毒的进化 触发主体组件的演变，反之亦然。例如，艾滋病毒已经适应了在人类细胞中生长， 部分原因是它已经适应了逃避人类的抗病毒抑制。在这个项目中， 过去慢病毒与其灵长类宿主的相互作用将用于指导功能和结构研究 艾滋病病毒与宿主蛋白质相互作用。 特别是，该项目利用宿主-病毒界面的遗传创新，其特征在于 轮回达尔文选择或积极选择。我们利用这种基因创新的进化特征 通过以下方法获得更有效地抑制HIV和更不易受拮抗作用影响的“超级限制因子”： 病毒蛋白通过测试宿主限制性因子库，在限制性因子库的位点上具有随机氨基酸变化， 正选择，可以衍生出具有新特性的宿主蛋白。最后，使用积极的标准 选择，将创建一个全基因组目录，用于优先考虑候选宿主蛋白质 作为全基因组遗传筛选或蛋白质-蛋白质相互作用研究的一部分， 通过提供一种评估这些相互作用是否已经 与病原体的进化冲突有关。

The human genome has evolved a constellation of antiviral genes with the potential to target HIV. However, the efficacy of these antiviral proteins fluctuates dynamically in evolutionary terms; evolution of the viruses triggers evolution of host components and vice-versa. For instance, HIV has adapted to grow in human cells, in part, because it has adapted to escape human antiviral inhibition. In this project, the evolutionary signatures of past interactions of lentiviruses with their primate hosts will be used to guide functional and structural studies of HIV-host protein interactions. In particular, this project exploits genetic innovation at the host-virus interface, characterized by signatures of recurrent Darwinian selection, or positive selection. We use evolutionary signatures of such genetic innovation to derive “super restriction factors” that are more potent at inhibiting HIV and less susceptible to antagonism by viral proteins. By testing libraries of host restriction factors with random amino acid changes at the sites of positive selection, host proteins with novel properties can be derived. Finally, using the criterion of positive selection, a whole genome catalog will be created that will be used to prioritize candidate host proteins identified as part of genome-wide genetic screens or protein-protein interaction studies for further biochemical studies in other Projects in this application by providing a means of assessing if these interactions have been involved in past evolutionary conflicts with pathogens.