HIV FACTORS AND CELLULAR INTERACTING PROTEIN PARTNERS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 人类先天免疫系统具有用于检测和攻击外来颗粒的大量策略，例如在感染人类免疫缺陷病毒（HIV）时引入的那些。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的防御系统。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反复出现的战斗主题。当HIV进入细胞时，它会遇到APOBEC 3G，这是一种抗病毒蛋白，它会诱导HIV DNA的广泛突变，使病毒不具有感染性。为了逃避DNA突变，HIV表达病毒体感染因子Vif，Vif结合APOBEC 3G并靶向其被蛋白酶体（细胞蛋白质循环机制）破坏。 该项目的总体目标是建立APOBEC 3G突变HIV DNA的化学和结构原理以及HIV Vif螯合APOBEC 3G的机制。这些目标将通过一个综合的方法来实现，该方法结合了酶促反应的动力学数据，蛋白质及其相互作用的生物物理特性，以及与关键底物和辅因子复合的蛋白质的原子分辨率结构。 从这些研究中获得的信息将用于指导基于结构的化合物设计，以抑制Vif并保护APOBEC 3G免受破坏。这些Vif抑制剂可能会导致一种新型的抗艾滋病毒药物，用于对抗艾滋病，这种流行病影响了全世界4000多万人。

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.