Identifying determinants of HIV-1 responsible for the nanoscale distribution and dynamics of virus assembly

确定负责病毒组装的纳米级分布和动态的 HIV-1 决定因素

• 批准号: 10391477
• 负责人: Schuyler van Engelenburg
• 金额: $ 35.45万
• 依托单位: UNIVERSITY OF DENVER (COLORADO SEMINARY)
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-10 至 2023-08-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391477
• 关键词: 3-Dimensional; Antiviral Therapy; Antiviral resistance; Biogenesis; Cell Line; Cell membrane; Cells; Cytoplasm; Cytoplasmic Tail; Data; Data Analytics; Diffuse; Drug Targeting; Elements; Endocytosis; Event; Exposure to; Genetic; Glycoproteins; Goals; HIV-1; Immune; Immune response; Immune system; Individual; Infection; Integral Membrane Protein; Integration Host Factors; Knowledge; Lead; Maps; Measurement; Measures; Membrane; Membrane Protein Traffic; Methods; Microscopy; Modeling; Molecular; Mutation; Pathway interactions; Peptides; Proteins; Recycling; Research; Role; Route; Scourge; Signal Transduction; Site; Societies; Sorting - Cell Movement; Structure; T-Lymphocyte; Viral; Virion; Virus; Virus Assembly; cell type; detection assay; detection platform; experimental study; gag Gene Products; human model; immunomodulatory strategy; immunomodulatory therapies; immunoregulation; in vivo; insight; molecular modeling; nanoscale; neutralizing antibody; pandemic disease; particle; pathogen; prevent; single molecule; spatiotemporal; stem; tool; trafficking

Project Summary The detailed mechanisms of Human Immunodeficiency Virus Type 1 (HIV-1) assembly constitute a significant gap in our understanding of the infection cycle of this devastating pathogen. Specifically, the mechanisms by which the essential Envelope (Env) glycoprotein and structural Gag molecule efficiently coalesce to form an infectious HIV-1 particle are poorly understood, due to our inability to quantitatively measure the spatiotemporal dynamics of individual molecules at the nanoscale within infected host cells. This proposal aims to delineate the underpinnings of HIV-1 assembly on a single molecule basis and in a native cellular context. To accomplish these aims, we propose to utilize superresolution microscopy to visualize and quantify the stages of virus assembly in order to determine the role of key peptide motifs found in HIV-1 Env and Gag. Our preliminary data and analytics demonstrate our ability to quantitatively map the biogenesis of HIV-1 and strongly suggest that this approach will provide unequivocal insight in the mechanisms of particle assembly. These discoveries will provide new quantitative models to guide approaches aimed at thwarting HIV-1 assembly.

项目摘要 人类免疫缺陷病毒1型（HIV-1）组装的详细机制 在我们对这种毁灭性的疾病的感染周期的理解中， 病原体特别是，必需的包膜（Env）糖蛋白和 结构性Gag分子很难有效地聚结形成感染性HIV-1颗粒， 理解，由于我们无法定量测量时空动态 在感染的宿主细胞内纳米级的单个分子。这项建议旨在界定 HIV-1在单分子基础上和在天然细胞环境中组装的基础。 为了实现这些目标，我们建议利用超分辨率显微镜来可视化和 量化病毒装配的阶段，以确定发现的关键肽基序的作用 HIV-1 Env和Gag。我们的初步数据和分析表明，我们有能力 定量绘制HIV-1的生物起源，并强烈表明这种方法将提供 对粒子组装机制的明确见解。这些发现将提供新的 定量模型来指导旨在阻止HIV-1组装的方法。