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The Vif-APOBEC Nexus

Vif-APOBEC Nexus

基本信息

批准号：
10327772
负责人：
Daniel James Salamango
金额：
$ 24.54万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-06 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10327772
关键词：
AIDS/HIV problem Amino Acid Substitution Antiviral Agents Bar Codes Binding Biochemistry CRISPR library Cells Cellular biology Clustered Regularly Interspaced Short Palindromic Repeats Complementary DNA Complex Coupled Cytosine deaminase DNA Deamination Defense Mechanisms Development Disease Progression Enzymes Event Family Gap Junctions Genetic Genome engineering Genomics Genotype Goals Guide RNA HIV Infections HIV-1 HIV-2 Human Immune Integration Host Factors Knowledge Lead Libraries Mediating Methods Modeling Molecular Mutation National Institute of Allergy and Infectious Disease Pathway interactions Patients Pharmaceutical Preparations Phase Post-Translational Regulation Proteins RNA Sequences Regulation Research Reverse Transcription Structure Substrate Interaction Surface System Techniques Technology Testing Therapeutic Viral Viral Genome Viral Packaging Viral reservoir Virion Virus Work curative treatments enzyme activity experimental study fundamental research innovation insight mRNA Differential Displays mutant next generation sequencing novel novel strategies particle programs restriction enzyme ubiquitin-protein ligase virology whole genome

项目摘要

The defining hallmark of A3-mediated restriction, explaining genomic plus strand G-to-A mutations in patient-derived viral sequences. However, the virus deploys a counteraction strategy that utilizes the virus encoded “virion infectivity factor” (Vif) to polyubiquitinate and degrade the A3s through a cellular E3-ubiquitin ligase complex. Here, I will use robust and unbiased experimental approaches to 1) identify separation-of-function Vif mutants that display differential activity against A3D and A3F restriction enzymes and 2) define the cellular mechanisms that regulate anti-HIV-1 activity of the A3s. My studies will utilize both hypothesis- and technology-driven approaches and a combination of fundamental virology, genetics/genome engineering, cell biology, and biochemistry techniques. I anticipate that a better understanding of the Vif/A3 surfaces and the underlying cellular mechanisms that govern A3 antiviral activity has the potential to lead to novel strategies to boost the anti-HIV-1 activities of these enzymes and contribute to the overall NIAID priority of “supporting innovative strategies for treating or curing HIV infection.”

A3 介导的限制的定义标志，解释了基因组正链 G 到 A 的突变患者来源的病毒序列。然而，该病毒部署了一种利用病毒的对抗策略编码“病毒粒子感染因子”(Vif)，通过细胞内多聚泛素化和降解 A3 E3-泛素连接酶复合物。在这里，我将使用稳健且公正的实验方法来 1）确定功能分离 Vif 突变体表现出针对 A3D 和 A3F 限制的不同活性酶和 2) 定义了调节 A3 的抗 HIV-1 活性的细胞机制。我的学业将利用假设和技术驱动的方法以及基础病毒学的结合，遗传学/基因组工程、细胞生物学和生物化学技术。我预计会有更好的了解 Vif/A3 表面和控制 A3 抗病毒的潜在细胞机制活性有可能导致新的策略来增强这些酶的抗 HIV-1 活性，并且为 NIAID 的总体优先事项“支持治疗或治愈 HIV 的创新策略”做出贡献感染。”