Dynamics of Gag-Pol auto-processing and ESCRT recruitment during HIV budding

HIV 萌芽期间 Gag-Pol 自动处理和 ESRT 招募的动态

• 批准号: 10222521
• 负责人: Saveez Saffarian
• 金额: $ 30.12万
• 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 2023-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222521
• 关键词: Antiviral Agents; Biochemical; Cell membrane; Cells; Color; Complex; Crowding; Data; Development; Diffusion; Dimerization; Ensure; Environment; Equine Infectious Anemia Virus; Evolution; Funding; Goals; HIV; HIV Budding; Image; Individual; Infection; Kinetics; Measures; Membrane; Methods; Molecular; Movement; Nature; Peptide Hydrolases; Permeability; Play; Polymers; Process; Protease Inhibitor; Proteins; Race; Regulation; Role; Sorting - Cell Movement; Surface; TSG101 gene; Testing; Time; TimeLine; Virion; base; density; equilibration disorder; experimental study; fluidity; in vivo; live cell imaging; recruit; vector

Project Summary: Our long-term goal is to gain a complete understanding of the molecular machinery that regulates the release of infectious HIV virions from infected cells. During our previous funding period (R21), we found that early Endosomal Sorting Complexes Required for Transport play a major role in a molecular race between virion budding and Gag-Pol auto-processing. We also found that disturbing the balance between budding and auto- processing results in release of non-infectious virions. In the face of rapid evolution of HIV under protease inhibitors, search for new target mechanisms to curb infections is crucial. Gag-Pol auto-processing and its regulation during assembly and budding present an intriguing target. Our fundamental understanding of this process however is limited due to its entanglement with assembly and budding kinetics and asynchronous nature of virion release. Here we propose to visualize HIV budding and Gag-Pol auto-processing in single virions in vivo to: 1) Establish the dynamics and regulation of early ESCRT recruitment during full HIV virion assembly, 2) Measure the dynamics of Gag-Pol incorporation and auto-processing during HIV budding and 3) Dissect the regulation of Gag-Pol auto-processing.

项目摘要： 我们的长期目标是完全了解调节释放的分子机制 感染细胞中的感染性HIV病毒体。在上一个融资期（R21），我们发现， 转运所需的内体分选复合物在病毒粒子之间的分子竞赛中起主要作用 出芽和Gag-Pol自动处理。我们还发现，扰乱萌芽和自动之间的平衡- 处理导致非感染性病毒体的释放。面对艾滋病毒蛋白酶下的快速进化 抑制剂，寻找新的目标机制，以遏制感染是至关重要的。Gag-Pol自动处理及其应用 在组装和出芽过程中的调控提出了一个有趣的目标。我们对此的基本理解 然而，由于其与组装和出芽动力学的纠缠以及异步 病毒粒子释放的性质。在这里，我们建议将HIV出芽和Gag-Pol自动处理可视化在单个 1）在完整的HIV病毒体期间建立早期ESCRT募集的动力学和调节 组装，2）测量HIV出芽过程中Gag-Pol掺入和自动加工的动力学，以及3） 剖析Gag-Pol自动加工的规律。