HIV Host-Cell Interactions

人类免疫缺陷病毒(HIV)是艾滋病的病原体，是一种复杂的逆转录病毒，具有 在简单的逆转录病毒中找不到的调节蛋白和辅助蛋白所赋予的控制水平。它是 继续研究辅助蛋白很重要，因为它们提供了潜在的抗病毒靶点，因为 它们教会了我们艾滋病毒复制的新步骤，因为它们为控制正常的宿主细胞提供了一个窗口 流程。近年来，艾滋病病毒辅助蛋白也变得很明显，可以作为应对措施 天生的细胞抗病毒机制。这项资助侧重于宿主细胞与病毒附件的相互作用。 蛋白质。 在这个提议中，我们试图了解病毒蛋白阻止细胞周期的选择性优势。 VPR与艾滋病毒有关。我们将批判性地检验这样一种假设，即选择G2阻止受到以下因素的影响 用竞争实验和小分子研究细胞周期阶段、病毒产生和细胞半衰期 VPR功能的抑制物。我们还将继续研究VPR阻止细胞周期的机制 通过它与宿主细胞蛋白质的相互作用。此外，VPR还与宿主细胞的DNA修复酶相互作用 称为尿嘧啶DNA糖苷酶(UNG)。由于UNG参与了由 APOBEC3蛋白是病毒Vif蛋白的靶标，我们将寻求了解TBE的交集 Vpr和Vif途径，并将确定UNG在病毒生命周期中的作用以及DNA修复在病毒中的作用 艾滋病毒的超突变。最后，我们已经开始应用进化生物学的方法来理解 抗病毒基因(APOBEC3家族)正向选择与HIV宿主细胞相互作用的研究 灵长类进化。这项工作将通过研究这一家族其他成员的进化来扩展 抗病毒基因，并通过系统发育分析评价Vif在灵长类慢病毒中的进化 并对其在灵长类动物中对APOBEC3蛋白的适应性进行了功能分析。预计这些结果： 将使我们更充分地了解病毒与其宿主的相互作用。

The human immunodeficiency virus (HIV), the causative agent of AIDS, is a complex retrovirus with levels of control imparted by regulatory and accessory proteins not found in simple retroviruses. it is important to continue to study the accessory proteins because they offer potential antiviral targets,because they teach us novel steps in HIV replication, and because they offer a window into control of normal host cell processes. In recent years it has also become clear that HIV accessory proteins serve as counter-measures to innate cellular antiviral mechanisms. This grant focuses on the interaction of the host cell with viral accessory proteins. In this proposal, we seek to understand the selective advantage that cell cycle arrest by the viralprotein Vpr confers on HIV. We will critically test the hypothesis that the selection for G2 arrest is influenced by cell cycle stage, virus production, and cell half-life using competition experiments and a smallmolecule inhibitor of Vpr function. We will also continue our study of the mechanism of cell cycle arrest by Vpr through its interaction with host cell proteins. In addition, Vpr interacts with a host cell DNA repair enzyme called Uracil DNA Glycosidase (UNG). Since UNG participates in the hypermutations induced by the Apobec3 proteins that are the target of the viral Vif protein, we will seek to understand the intersection of tbe Vpr and Vif pathways and will determine the role of UNG in the viral life cycle and the role of DNA repair in HIV hypermutation. Finally, we have begun to apply an evolutionary biology approach to understanding HIV host cell interactions by studying the positive selection of antiviral genes (the Apobec3 family) during primate evolution. This work will be extended by studying the evolution of other members of this family of antiviral genes, and by evaluating the evolution of Vif among the primate lentiviruses through phylogenetic and functional analysis of its adaptation to Apobec3 proteins in primates. It is anticipated that these: results will allow us to more fully understand the interaction of the virus with its host.