Architecture and dynamics of immature HIV lattice

未成熟HIV晶格的结构和动力学

• 批准号: 10866707
• 负责人: Saveez Saffarian
• 金额: $ 45.23万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10866707
• 关键词: Affect; Antiviral Agents; Architecture; Atomic Force Microscopy; Award; Binding; Biochemical; Biomechanics; CASP1 gene; Capsid; Computing Methodologies; Cone; Development; Diffusion; Disease; Enzymes; Experimental Designs; Funding; Future; Geometry; Goals; Guide RNA; HIV; HIV Protease; Individual; Integrase; Kinetics; Knowledge; Link; Measurement; Measures; Membrane; Methods; Microscopic; Molecular; Nature; Open Reading Frames; Peptide Hydrolases; Prevalence; Process; Proteins; Proteolysis; RNA-Directed DNA Polymerase; Residual state; Role; Signal Transduction; Structure; System; Testing; Vertebral column; Viral; Virion; Virus; biophysical techniques; cofactor; design; dimer; equilibration disorder; gag Gene Products; gag-pol Fusion Proteins; imaging modality; inhibitor; monomer; next generation; pol Gene Products

Project Summary: Our long-term goal is to gain a molecular understanding of the machinery that regulates the assembly, release, and maturation of infectious HIV virions. Newly released HIV virions are immature and have a lattice of proteins (mainly the Gag polyprotein) that underpins their viral membrane. Through proteolysis, HIV enzymes help transform this lattice into a conical mature core, after which the virus becomes infectious. Maturation Inhibitors, a new class of antiviral drugs, are designed to bind to the immature lattice and interfere with this transformation. During the previous award period, we showed that the stability of the immature lattice is dependent on other HIV components aside from the Gag polyprotein. The small size of HIV virions makes studying their lattice dynamics challenging, therefore, we developed biophysical, imaging, and computational methods to enable these measurements. We have two main aims for this award period. Our first aim is to investigate the specific effects of different non-Gag components on the stability of the immature lattice and determine the nature of biomolecular forces stabilizing it. Our second aim is to determine how dynamics within the lattice drive the activation of HIV enzymes and kick start the maturation process. By advancing our understanding of the biomechanical principles governing the immature lattice of HIV and its maturation, our studies will inform both the design of next- generation antivirals as well as future lentiviral systems.

项目摘要： 我们的长期目标是对调节组装，释放，，， 感染性艾滋病毒病毒体的成熟。新发布的HIV病毒不成熟，具有蛋白质的晶格 （主要是GAG多蛋白），该蛋白支撑了其病毒膜。通过蛋白水解，HIV酶有助 将此晶格转变为圆锥体成熟的核心，此后病毒变得感染力。成熟抑制剂， 一类新的抗病毒药物旨在与未成熟的晶格结合并干扰这种转化。 在上一个奖项期间，我们表明未成熟晶格的稳定性取决于其他艾滋病毒 除了GAG多蛋白外，成分。艾滋病毒的小尺寸使研究其晶格动力学 因此，具有挑战性，我们开发了生物物理，成像和计算方法来实现这些方法 测量。我们在此奖项时期有两个主要目标。我们的第一个目的是调查特定效果 关于未成熟晶格的稳定性的不同非GAG成分的数量，并确定生物分子的性质 强迫稳定它。我们的第二个目的是确定晶格中的动态如何驱动HIV的激活 酶并启动开始成熟过程。通过促进我们对生物力学原理的理解 管理艾滋病毒及其成熟的未成熟晶格及其成熟，我们的研究将为接下来的设计介绍 一代抗病毒药以及未来的慢病毒系统。