Late Events in Retrovirus Assembly

逆转录病毒组装中的晚期事件

• 批准号: 7870365
• 负责人: Paul D. Bieniasz
• 金额: $ 33.57万
• 依托单位: AARON DIAMOND AIDS RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7870365
• 关键词: Binding Proteins; Biogenesis; Cell physiology; Cells; Clathrin; Disease; Endocytosis; Endosomes; Event; Funding; Goals; Grant; HIV; HIV-1; Infection; Life; Mediating; Multivesicular Body; Pathway interactions; Process; Proteins; Recruitment Activity; Request for Applications; Retroviridae; Role; Site; Sorting - Cell Movement; Staging; System; Ubiquitin; Vacuolar Protein Sorting; Viral; Virion; Virus; Work; novel; particle; public health relevance; therapeutic target; trafficking; ubiquitin ligase

DESCRIPTION (provided by applicant): In this competing renewal application we request support for our studies on late events in retrovirus assembly. In the previous funding cycle, we identified and characterized several cellular proteins that are recruited to sites of retrovirus assembly by viral late budding (L)-domains. These proteins are either (i) components of the class E vacuolar protein sorting (VPS) pathway that is normally involved in the manipulation of endosomes and multivesicular bodies (MVB) or (ii) ubiquitin ligases. For several of these factors we were able to demonstrate a critical role in the release of infectious retroviral particles. Several mechanistic questions remain, however, and recently we have identified additional cellular factors that seem very likely to be involved in the late stages of the construction and release of retrovirus particles, and/or endosome/MVB biogenesis. In the next grant period, we will attempt to elucidate how previously defined and newly identified cellular factors participate in the late stages of retrovirus assembly and related cellular functions by pursuing two specific aims. Specific Aim 1 is to understand how specific endosomal proteins are incorporated into HIV-1 particles and their role in generating infectious virions. Specific aim 2 is to determine the role of ubiquitin, ubiquitin ligases and novel ubiquitin ligase binding proteins, discovered during the previous funding period, in retroviral budding and trafficking of endocytosed proteins. Execution of these two aims should result in significant progress toward our long term goal of understanding how cellular and viral factors cooperate in the construction of complete, infectious retroviral particles. Understanding these events could potentially provide new opportunities to interfere in these processes for the treatment of diseases caused by HIV and other enveloped viruses. Public health relevance: Many enveloped viruses, for example HIV-1, are responsible for life threatening infections. To spread from cell to cell they make use of cellular proteins to facilitate the release of accurately assembled virus particles. Understanding how this system works could give opportunities to intervene with targeted therapeutics.

描述（由申请人提供）：在这个竞争性更新申请中，我们请求支持我们关于逆转录病毒组装晚期事件的研究。在上一个资助周期中，我们鉴定并表征了几种细胞蛋白，这些蛋白通过病毒晚出芽（L）结构域被招募到逆转录病毒组装位点。这些蛋白质要么是 (i) E 类液泡蛋白分选 (VPS) 途径的组成部分，该途径通常参与内体和多泡体 (MVB) 的操作，要么是 (ii) 泛素连接酶。对于其中的几个因素，我们能够证明在传染性逆转录病毒颗粒的释放中发挥着关键作用。然而，仍然存在一些机制问题，最近我们发现了其他细胞因素，这些因素似乎很可能参与逆转录病毒颗粒构建和释放的后期阶段，和/或内体/MVB 生物发生。在下一个资助期内，我们将尝试通过追求两个特定目标来阐明先前定义的和新识别的细胞因子如何参与逆转录病毒组装的后期阶段和相关的细胞功能。具体目标 1 是了解特定内体蛋白如何整合到 HIV-1 颗粒中以及它们在产生感染性病毒颗粒中的作用。具体目标 2 是确定上一个资助期间发现的泛素、泛素连接酶和新型泛素连接酶结合蛋白在逆转录病毒出芽和内吞蛋白运输中的作用。这两个目标的实现应该会在实现我们的长期目标方面取得重大进展，即了解细胞和病毒因子如何在构建完整的感染性逆转录病毒颗粒过程中合作。了解这些事件可能会为干预这些过程以治疗艾滋病毒和其他包膜病毒引起的疾病提供新的机会。公共卫生相关性：许多包膜病毒，例如 HIV-1，会导致危及生命的感染。为了从一个细胞传播到另一个细胞，它们利用细胞蛋白来促进精确组装的病毒颗粒的释放。了解该系统的工作原理可以为干预靶向治疗提供机会。