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

• 批准号: 9176518
• 负责人: SUSAN R ROSS
• 金额: $ 20.8万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 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/9176518
• 关键词: Role; APOBEC3; vivo; Restriction; Retrovirus

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-resistanct 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 variants of retroviruses and other viruses. 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）：传染剂在整个进化过程中都感染了原核生物和真核生物。的确，生物体及其感染因子之间存在着共同的进化，并在宿主中发展了保护性反应，并由传染性药物对它们进行了适应性的对策。载脂蛋白B编辑复合蛋白3（A3）蛋白家族赋予了一种病毒限制系统，该蛋白质脱氨酸在单链DNA中脱氧脱氧胞苷的残基，从而导致GC-to-to AT转变。 A3基因在拷贝数和序列方面都是高度多态性的，并且显示出阳性选择的强烈证据，表明它们在响应感染因素（如病毒）类似地，逆转录病毒和其他病毒表现出脱氨基脚印，表明它们反过来又表明它们在A3蛋白下及其在A3蛋白下的脱氨基脱位，并且可以使A3介导的DNA持续脱离，并提出了脱氨基的影响。变体。尽管已经了解了A3蛋白及其在病毒限制中的作用，但大多数研究都是在培养的细胞中进行的，通常使用过度表达的蛋白质以及对从患者组织中分离出的病毒或人类原代细胞中实验的病毒的序列分析，存在7种人类A3基因，其中许多人在同一细胞类型中表达。实际上，尽管A3b，A3D，A3F，A3G和A3H都限制了HIV和其他病毒，但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蛋白如何通过逆转录病毒限制感染。我们已经开发了敲除小鼠，以及最近通过基因工程的动物来表达人类A3蛋白，以研究小鼠乳腺肿瘤病毒和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单个人类A3蛋白如何在体内感染，塑造病毒进化并影响免疫逃逸和逆转录病毒和其他病毒的耐药变体的发展中。因此，这些研究将增加我们对A3蛋白在体内作用机理的理解，并为测试抗病毒药物疗法提供模型。