HIV FACTORS AND CELLULAR INTERACTING PROTEIN PARTNERS

HIV 因子和细胞相互作用蛋白伙伴

• 批准号: 8170663
• 负责人: Yong Xiong
• 金额: $ 1.89万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170663
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Antiviral Agents; Binding; Biochemical Reaction; Cells; Chemicals; Complex; Computer Retrieval of Information on Scientific Projects Database; Crystallography; Data; Funding; Gene Mutation; Goals; Grant; HIV; Host Defense; Human; Immune response; Immune system; Infection; Institution; Kinetics; Lead; Methods; Mutate; Mutation; Pharmaceutical Preparations; Proteins; Recycling; Research; Research Personnel; Resolution; Resources; Source; Structure; System; United States National Institutes of Health; Virion; Virus; Virus Diseases; base; cofactor; design; fighting; inhibitor/antagonist; multicatalytic endopeptidase complex; novel; pandemic disease; particle; protein structure; viral DNA

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 人类先天免疫系统具有广泛的战术曲目，这些策略旨在检测和攻击异物颗粒，例如在感染人类免疫缺陷病毒（HIV）时引入的颗粒。反过来，艾滋病毒又开发了一种同样令人印象深刻的方法来逃避宿主防御系统。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这种反复出现的主题。当艾滋病毒进入细胞时，它会遇到抗病毒蛋白的apobec3g，该蛋白会诱导HIV DNA中广泛的突变，从而使病毒不感染。为了避免DNA突变，HIV表示结合Apobec3g并将其靶向蛋白酶体，即细胞蛋白回收机械的销毁。 该项目的总体目标是建立APOBEC3G突变HIV DNA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，该方法结合了有关酶促反应动力学，蛋白质及其相互作用的生物物理表征以及蛋白质与关键底物和辅助因子复合物中的原子分辨率结构的数据。 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，这些化合物抑制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HIV药物来对抗艾滋病，这是全球影响超过4000万人的大流行。