Project 1. Maturation and Assembly

项目1--艾滋病毒-1成熟和组装 这个项目的总体目标是确定和开发关键的、潜在的可下药的复合体和相互作用 在HIV-1组装和成熟过程中存在的，包括Gag及其成熟中间体，病毒 核糖核蛋白(VRNP)复合体，与基质(MA)-糖蛋白41(Gp41)胞浆尾部相互作用。这个 拟议的研究是11名PCHPI调查人员和四个核心(核磁共振、CryoEM/ET、 计算和艾滋病毒病毒学)。具体目的是为了：1)了解分子、生化、 成熟抑制物(MI)和变构整合酶抑制物(Allini)活性和抗性的结构基础 途径；ii)确定病毒核糖核蛋白复合体(VRNPs)中RNA和蛋白质的组织结构 成熟的特定阶段；以及iii)描述GAG的MA结构域与 Gp41的胞质尾巴。通过拟议工作获得的结构和机械知识将使 具有改进的抗病毒效力的新型MI和ALLINI的开发和潜在的指导方法 抑制HIV-1vRNPs和MA-gp41复合体中的蛋白质相互作用。

Project 1 – HIV-1 Maturation and Assembly The overall goal of this project is to identify and exploit key, potentially druggable complexes and interactions that are present during HIV-1 assembly and maturation, including Gag and its maturation intermediates, the viral ribonucleoprotein (vRNP) complex, and the matrix (MA)-glycoprotein 41 (gp41) cytoplasmic tail interaction. The proposed studies are an integrated effort from 11 PCHPI investigators and four cores (NMR, CryoEM/ET, Computational, and HIV Virology). The specific aims are designed to i) understand the molecular, biochemical, and structural basis for maturation inhibitor (MI) and allosteric integrase inhibitor (ALLINI) activity and resistance pathways; ii) define the organization of RNA and proteins in the viral ribonucleoprotein complex (vRNPs) and at specific stages of maturation; and iii) characterize the interaction between the MA domain of Gag and the cytoplasmic tail of gp41. The structural and mechanistic knowledge gained through the proposed work will inform the development of novel MIs and ALLINIs with improved antiviral potency and potentially guide approaches to inhibit protein interactions in HIV-1 vRNPs and in MA-gp41 complexes.