Role of APOBEC3 in in vivo Restriction of Retrovirus Infection

APOBEC3 在体内限制逆转录病毒感染中的作用

基本信息

批准号：
9054058
负责人：
SUSAN R ROSS
金额：
$ 39.95万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9054058
关键词：
Address Affect Animals Anti-Retroviral Agents Antiretroviral drug resistance Antiviral Agents Antiviral Response Apolipoproteins B Biology Cells Complex Cultured Cells Cytidine Cytidine Deaminase Deamination Deoxycytidine Development Drug resistance Endogenous Retroviruses Eukaryota Evolution Genes Genetic Engineering HIV HIV-1 Haplotypes Health Hepatitis B Virus Herpesviridae Human Human Papillomavirus Immune Individual Infection Infection Control Infectious Agent Knock-out Knockout Mice Knowledge Lead Learning Mediating Modeling Mouse Mammary Tumor Virus Murine leukemia virus Mus Organism Parvovirus Patients Pharmacotherapy Prokaryotic Cells Protein Family Protein Sequence Analysis Proteins Research Resistance Retroviridae Retroviridae Infections Role Sequence Analysis Shapes Single-Stranded DNA Spumavirus System Testing Tissues Transgenic Mice Variant Viral Viral Genome Virus Virus Diseases antiviral immunity base cell type in vivo mouse model novel pressure prevent protein function research study response tissue/cell culture tool viral DNA viral fitness viral transmission

项目摘要

DESCRIPTION (provided by applicant): Infectious agents have infected prokaryotes and eukaryotes throughout evolution. Indeed, there is co-evolution among organisms and their infectious agents, with development of protective responses in the hosts and adaptive countermeasures to them by the infectious agents. One system of viral restriction is conferred by the Apolipoprotein B editing complex 3 (A3) family of proteins, which deaminate deoxycytidine residues in single-stranded DNA leading to GC-to-AT transitions. A3 genes are highly polymorphic both with regard to copy number and sequence and show strong evidence of positive selection, indicating that they are evolving in response to infectious agents like viruses Similarly, retroviruses and other viruses show deamination footprints suggesting they in turn are under selective pressure by A3 proteins and it has been suggested that A3-mediated deamination of viral DNA could lead to both drug-resistant and immune escape variants. While much has been learned about A3 proteins and their roles in virus restriction, most studies have been carried out in cultured cells, often using over- expressed proteins and sequence analysis of viruses isolated from patient tissue or experiments in human primary cells are complicated by the presence of 7 human A3 genes, many of which are expressed in the same cell types. Indeed while A3B, A3D, A3F, A3G and A3H all restrict HIV and other viruses when over-expressed, there role in control of infection in vivo remains unclear. Our lab pioneered the use of in vivo mouse models to study how A3 proteins restrict infection by retroviruses. We have developed knockout mice and more recently genetically engineered animals that express individual human A3 proteins to study infection by mouse mammary tumor virus and murine leukemia virus. Here, we propose to use these mouse models to study how individual human A3 proteins function in to restrict in vivo infection, shape virus evolution and affect the developmen of immune escape and drug-resistant retroviruses. These studies will thus add to our understanding of A3 proteins mechanism of action in vivo as well as provide models for testing anti-viral drug therapies.

描述（由申请人提供）：感染原在整个进化过程中感染了原核生物和真核生物。事实上，随着宿主的保护性反应和感染原的适应性对策的发展，生物体及其感染原之间存在着共同进化。病毒限制系统由载脂蛋白 B 编辑复合物 3 (A3) 蛋白家族赋予，该蛋白使单链 DNA 中的脱氧胞苷残基脱氨基，从而导致 GC 至 AT A3 基因在拷贝数和序列方面都具有高度多态性，并显示出强有力的正选择证据，表明它们正在进化以响应病毒等感染因子，类似地，逆转录病毒和其他病毒显示出脱氨基足迹，表明它们反过来也受到影响。 A3 蛋白的选择性压力，有人认为 A3 介导的病毒 DNA 脱氨基可能导致耐药性和免疫逃逸变异。出入培养的细胞，通常使用从患者组织或人类原代细胞中分离的病毒的过表达蛋白质和序列分析，由于 7 个人类 A3 基因的存在而变得复杂，其中许多基因在相同的细胞类型中表达，而 A3B， A3D、A3F、A3G 和 A3H 在过度表达时都会限制 HIV 和其他病毒，但其在体内控制感染中的作用仍不清楚。我们的实验室率先使用体内小鼠模型来研究 A3 如何限制逆转录病毒的蛋白质感染。已经开发出基因敲除小鼠和最近表达个体人类 A3 蛋白的基因工程动物，以研究小鼠乳腺肿瘤病毒和小鼠白血病病毒的感染。在这里，我们建议使用这些小鼠模型来研究个体人类 A3 如何在体内发挥作用。因此，这些研究将加深我们对 A3 蛋白体内作用机制的理解，并为测试抗病毒药物疗法提供模型。