HIV FACTORS AND CELLULAR INTERACTING PROTEIN PARTNERS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 人类的先天免疫系统有大量用于检测和攻击外来颗粒的策略，例如感染人类免疫缺陷病毒(HIV)时引入的那些颗粒。反过来，艾滋病毒也发展出了同样令人印象深刻的方法来逃避宿主防御系统。一种新发现的先天免疫反应突出了宿主生存和病毒感染之间的斗争这一反复出现的主题。当HIV进入细胞时，它会遇到APOBEC3G，一种抗病毒蛋白，它会导致HIV DNA的广泛突变，使病毒不具传染性。为了躲避DNA突变，HIV表达了病毒粒子感染性因子Vif，该因子结合APOBEC3G，并将其作为目标，通过细胞蛋白质回收机制蛋白酶体进行破坏。该项目的总体目标是建立APOBEC3G使HIV DNA突变的化学和结构原理，以及HIV Vif隔离APOBEC3G的机制。这些目标将通过一种综合方法来实现，该方法结合了酶反应动力学、蛋白质及其相互作用的生物物理特征以及具有关键底物和辅因子的复合体中蛋白质的原子分辨结构的数据。从这些研究中获得的信息将被用于指导基于结构的化合物设计，以抑制VIF并保护APOBEC3G免受破坏。这些Vif抑制剂可能会导致一类新型的抗艾滋病毒药物来对抗艾滋病，艾滋病是一种影响全球4000多万人的流行病。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The human innate immune system has a vast repertoire of tactics that are engaged to detect and attack foreign particles, such as those introduced upon infection with human immunodeficiency virus (HIV). HIV, in turn, has developed an equally impressive arsenal of methods to evade the host defense system. A newly discovered innate immune response highlights this recurring theme of battle between host survival and viral infection. When HIV enters a cell, it encounters APOBEC3G, an antiviral protein, which induces extensive mutations in the HIV DNA to render the virus non-infectious. To elude the DNA mutation, HIV expresses the virion infectivity factor, Vif, which binds APOBEC3G and targets it for destruction by the proteasome, the cellular protein recycling machinery. The overall goal of this project is to establish the chemical and structural principles by which APOBEC3G mutates HIV DNA and the mechanisms by which HIV Vif sequesters APOBEC3G. These objectives will be achieved through an integrated approach that combines data on the kinetics of the enzymatic reaction, biophysical characterization of the proteins and their interactions, and atomic resolution structures of the proteins in complex with key substrates and cofactors. Information gained from these studies will be used to direct structure-based design of chemical compounds that inhibit Vif and protect APOBEC3G from destruction. These Vif inhibitors may lead to a novel class of anti-HIV drugs that fight AIDS, the pandemic affecting over 40 million people worldwide.