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: 10405685
• 负责人: Saveez Saffarian
• 金额: $ 7万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405685
• 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.

项目概要： 我们的长期目标是全面了解调节释放的分子机制 来自受感染细胞的传染性 HIV 病毒粒子。在我们之前的资助期 (R21) 中，我们发现早期 运输所需的内体分选复合物在病毒粒子之间的分子竞赛中发挥着重要作用 萌芽和 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粒子的释放。面对蛋白酶作用下HIV的快速进化 抑制剂，寻找新的靶点机制来抑制感染至关重要。 Gag-Pol自动处理及其 组装和萌芽过程中的调节是一个有趣的目标。我们对此的基本认识 然而，由于其与组装和出芽动力学以及异步的纠缠，该过程受到限制 病毒粒子释放的性质。在这里，我们建议在单个过程中可视化 HIV 出芽和 Gag-Pol 自动处理 体内病毒粒子：1) 建立完整 HIV 病毒粒子期间早期 ESRT 募集的动态和调节 组装，2) 测量 HIV 萌芽期间 Gag-Pol 掺入和自动处理的动态，以及 3) 剖析 Gag-Pol 自动处理的规定。

项目成果

Gag-Gag Interactions Are Insufficient to Fully Stabilize and Order the Immature HIV Gag Lattice.

• DOI: 10.3390/v13101946
• 发表时间: 2021-09-28
• 期刊: Viruses
• 作者: Saha I;Preece B;Peterson A;Durden H;MacArthur B;Lowe J;Belnap D;Vershinin M;Saffarian S
• 通讯作者: Saffarian S

Abrogating ALIX Interactions Results in Stuttering of the ESCRT Machinery.

• DOI: 10.3390/v12091032
• 发表时间: 2020-09-16
• 期刊: Viruses
• 作者: Gupta S;Bendjennat M;Saffarian S
• 通讯作者: Saffarian S

Application of Advanced Light Microscopy to the Study of HIV and Its Interactions with the Host.

• DOI: 10.3390/v13020223
• 发表时间: 2021-02-01
• 期刊: Viruses
• 作者: Saffarian S