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: 10647648
• 负责人: Molly OhAinle
• 金额: $ 40.13万
• 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/10647648
• 关键词: Binding; Biochemical; Biological Assay; Biomedical Research; CRISPR screen; Candidate Disease Gene; Capsid; Capsid Proteins; Cells; Cercopithecidae; Clustered Regularly Interspaced Short Palindromic Repeats; Complement; Cytotoxic T-Lymphocytes; Dependence; Disease; Disease Outbreaks; Escape Mutant; Evolution; Follow-Up Studies; Genes; Genetic; Genetic Transcription; HIV; HIV Genome; HIV Infections; HIV therapy; HIV-1; Human; Individual; Infection; Integration Host Factors; Interferons; Invaded; Lentivirus; Life Cycle Stages; Mediating; Methodology; Nuclear; Play; Primate Lentiviruses; Primates; Proteins; Role; SIV; Shapes; TRIM5 gene; Technology; Testing; Variant; Viral; Viral Genes; Viral Genome; Virus; Virus Replication; Work; antagonist; cross-species transmission; gene induction; genome-wide; improved; in vivo; integration site; interest; mutant; novel; obligate intracellular parasite; pandemic disease; paralogous gene; pressure; programs; tool; transmission process; whole genome

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.

项目总结： 作为一种专性的细胞内寄生虫，艾滋病毒和所有病毒一样，依赖于宿主编码的因子来 在宿主细胞内完成其生命周期。然而，该病毒还必须通过以下方式逃避识别 专门的宿主因子，专门进化来保护细胞免受病毒入侵。 一些抗病毒基因是干扰素诱导的转录程序的一部分 由宿主在感知到病毒入侵时部署。寄主基因的全面描述 阻止灵长类慢病毒成功感染人类细胞的方法 用当前的方法进行表征。在目标1中，我们将描述 对HIV-1及相关灵长类猴免疫缺陷病毒(SIV)变异株的抑制作用 TRIM34，我们发现的一种TRIM5 Paralog，专门针对HIV-1衣壳变异体和 SIV。在目标2中，我们将探索TRIM34作为广泛作用的抗病毒基因在灵长类动物中的作用。 以及TRIM34在限制HIV-1感染进化方面的潜在作用 在主机内。在目标3中，我们将进行全基因组HIV-CRISPR筛查方法 寻找抑制HIV-1衣壳突变体的干扰素刺激基因(ISGs)。除了……之外 在人类细胞中通过TRIM34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毒株在人类细胞中复制。 后续研究将集中于加深我们对黄连的作用机制的了解。 感兴趣的基因以及病毒拮抗或逃逸机制。归根结底，操纵 这些因素中的一部分对于旨在实现有效的艾滋病毒治疗的方法可能是重要的。

项目成果

Patterns of Evolution of TRIM Genes Highlight the Evolutionary Plasticity of Antiviral Effectors in Mammals.

• DOI: 10.1093/gbe/evad209
• 发表时间: 2023-12-01
• 期刊: GENOME BIOLOGY AND EVOLUTION
• 影响因子: 3.3
• 作者: Fernandes, Alexandre P.;OhAinle, Molly;Esteves, Pedro J.
• 通讯作者: Esteves, Pedro J.

Identification of DAXX as a restriction factor of SARS-CoV-2 through a CRISPR/Cas9 screen.

• DOI: 10.1038/s41467-022-30134-9
• 发表时间: 2022-05-04
• 期刊: Nature communications
• 影响因子: 16.6

A balancing act between primate lentiviruses and their receptor.

灵长类慢病毒及其受体之间的平衡作用。

• DOI: 10.1073/pnas.2104741118
• 发表时间: 2021
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Ohainle,Molly;Malik,HarmitS
• 通讯作者: Malik,HarmitS