Discovery and Characterization of Capsid-Targeting Lentiviral Restriction Factors

衣壳靶向慢病毒限制因子的发现和表征

• 批准号: 10659552
• 负责人: Molly OhAinle
• 金额: $ 31.26万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-14 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10659552
• 关键词: Discovery; Characterization; Capsid; Targeting; Lentiviral

Project Summary: As an obligate intracellular parasite HIV, like all viruses, relies on host-encoded factors to complete its life cycle inside the host cell. However, the virus must also evade recognition by specialized host factors that have evolved specifically to defend cells against viral invasion. Some of the antiviral genes are part of an Interferon-induced transcriptional program that is deployed by the host on sensing of a viral invader. A comprehensive description of host genes that block primate lentiviruses from successfully infecting human cells has evaded characterization with current methodologies. In Aim 1 we will describe the mechanism of inhibition of HIV-1 and related primate Simian Immunodeficiency Virus (SIV) variants by TRIM34, a TRIM5 paralog we have discovered to specifically target HIV-1 capsid variants and SIVs. In Aim 2 we will explore the role of TRIM34 as a broadly acting antiviral gene in primates as well as the potential role of TRIM34 in contributing to limiting the evolution of HIV-1 infections within the host. In Aim 3 we will perform a whole-genome HIV-CRISPR screening approach to find the Interferon-Stimulated Genes (ISGs) that inhibit HIV-1 capsid mutants. In addition to defining a novel HIV restriction by TRIM34 in human cells, this work has the potential to discover novel host antiviral genes that limit SIV and HIV strains from replicating in human cells. Follow-up studies will be focused on furthering our understanding the mechanism of action of genes of interest as well as mechanisms of viral antagonism or escape. Ultimately, manipulation of these factors could be important for approaches aimed at achieving a functional HIV cure.

项目概要： 作为一种专性细胞内寄生虫，HIV 与所有病毒一样，依赖宿主编码因子来传播病毒。 在宿主细胞内完成其生命周期。然而，病毒也必须逃避识别 专门进化来保护细胞免受病毒入侵的特殊宿主因子。 一些抗病毒基因是干扰素诱导的转录程序的一部分，该程序是 由宿主在感知到病毒入侵者时部署。宿主基因的全面描述 阻止灵长类慢病毒成功感染人类细胞的方法已被逃脱 使用当前方法进行表征。在目标 1 中，我们将描述其机制 抑制 HIV-1 和相关灵长类猴免疫缺陷病毒 (SIV) 变种 TRIM34，我们发现的 TRIM5 旁系同源物，专门针对 HIV-1 衣壳变体， SIV。在目标 2 中，我们将探讨 TRIM34 作为灵长类动物中广泛作用的抗病毒基因的作用 以及 TRIM34 在限制 HIV-1 感染进化方面的潜在作用 主机内。在目标 3 中，我们将采用全基因组 HIV-CRISPR 筛查方法来 找到抑制 HIV-1 衣壳突变体的干扰素刺激基因 (ISG)。此外 通过 TRIM34 在人类细胞中定义了一种新的 HIV 限制，这项工作有可能 发现新的宿主抗病毒基因，限制 SIV 和 HIV 病毒株在人体细胞中复制。 后续研究将侧重于进一步了解其作用机制 感兴趣的基因以及病毒拮抗或逃逸的机制。最终，操纵 这些因素对于实现艾滋病毒功能性治愈的方法可能很重要。