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.

项目概要： 我们的长期目标是获得对调节组装、释放、 以及传染性 HIV 病毒体的成熟。新释放的 HIV 病毒体尚未成熟，具有蛋白质晶格 （主要是 Gag 多蛋白）支撑病毒膜。 HIV 酶通过蛋白水解作用帮助 将这个晶格转变为圆锥形的成熟核心，之后病毒就具有传染性。成熟抑制剂， 一类新型抗病毒药物旨在与未成熟的晶格结合并干扰这种转变。 在上一个奖项期间，我们证明了未成熟晶格的稳定性依赖于其他HIV 除 Gag 多蛋白外的其他成分。 HIV 病毒体的小尺寸使得研究其晶格动力学成为可能 因此，我们开发了生物物理、成像和计算方法来实现这些 测量。我们在此奖励期有两个主要目标。我们的首要目标是研究具体效果 不同非Gag组分对未成熟晶格稳定性的影响并确定生物分子的性质 力使其稳定。我们的第二个目标是确定晶格内的动力学如何驱动 HIV 的激活 酶并启动成熟过程。通过增进我们对生物力学原理的理解 控制艾滋病毒的不成熟晶格及其成熟，我们的研究将为下一步的设计提供信息 一代抗病毒药物以及未来的慢病毒系统。