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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：
8420340
负责人：
SUSAN R ROSS
金额：
$ 36.68万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8420340
关键词：
Affect Antiviral Agents Apolipoproteins B B-Lymphocytes Biological Models Cells Complex Cultured Cells Cytidine Cytosine DNA Deamination Dependovirus Development Epithelial Cells Eukaryota Evolution Family Gene Deletion Genes Genetic Polymorphism Genome HIV HIV Infections HIV-1 Hepatitis B Virus Human Human Genome Human Papillomavirus Immune In Vitro Infection Infection Control Infectious Agent Knockout Mice Lactation Lymphoid Lymphoid Tissue Mammary gland Mediating Milk Monkeys Mouse Mammary Tumor Virus Mus Organism Pathway interactions Play Prokaryotic Cells Protein Family Proteins Retroviridae Retroviridae Infections Role SIV Spumavirus System T-Lymphocyte Tissues Tumor Virus Infections Viral Viral Physiology Virion Virus Virus Diseases Virus Replication base human CEM15 protein human tissue in vivo insight interest mouse model protein function public health relevance research study response transmission process

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 recently identified system of viral restriction is the Apolipoprotein B editing complex (APOBEC or A) family of proteins. Human APOBEC3G was first identified as an anti-viral factor in HIV infection. The human genome encodes multiple A3 proteins, including hA3G and hA3F. hA3G and hA3F restrict infection by Vif-deficient human immunodeficiency virus 1 (HIV-1). A3 proteins are packaged into virions and inhibit retroviral replication in newly infected cells, in part by deaminating cytosines on negative strand DNA intermediates and through as of yet uncharacterized mechanisms. We recently provided the first in vivo demonstration of an antiviral function for A3 proteins. We showed that mouse mammary tumor virus (MMTV) replication was inhibited by endogenous mA3 in vivo, since mice with targeted deletion of this gene were more susceptible to infection than their wild type littermates. We also showed that hA3G was packaged into MMTV virions and inhibited infection of cultured cells. We propose here to use MMTV to further probe the function of mA3 and hA3 proteins. We will examine the mechanism by which A3 proteins are packaged into virions, restrict retrovirus infection in vitro and in vivo, the role that polymorphisms in the A3 genes plays in affecting virus restriction and whether A3 expression in mammary tissue restricts milk-borne transmission of virus. As a consequence of these studies, we will know what role/s A3 proteins play in infection by exogenous viruses. These studies will provide a basis for understanding how this family of intrinsic immune factors inhibits viral infection of the mouse and other species by exogenous viruses, including HIV-1 infection of humans.

描述（由申请人提供）：传染源在整个进化过程中感染了原核生物和真核生物。事实上，生物体及其传染原之间存在着共同进化，随着宿主的保护性反应的发展以及传染原对它们的适应性对策。最近发现的一种病毒限制系统是载脂蛋白 B 编辑复合物（APOBEC 或 A）蛋白家族。人类 APOBEC3G 首次被鉴定为 HIV 感染的抗病毒因子。人类基因组编码多种 A3 蛋白，包括 hA3G 和 hA3F。 hA3G 和 hA3F 限制 Vif 缺陷型人类免疫缺陷病毒 1 (HIV-1) 的感染。 A3 蛋白被包装到病毒体中，并抑制新感染细胞中的逆转录病毒复制，部分是通过负链 DNA 中间体上的胞嘧啶脱氨基以及通过尚未表征的机制。我们最近首次在体内证明了 A3 蛋白的抗病毒功能。我们发现，小鼠乳腺肿瘤病毒（MMTV）的复制在体内受到内源性 mA3 的抑制，因为定向删除该基因的小鼠比其野生型同窝小鼠更容易受到感染。我们还表明，hA3G 被包装到 MMTV 病毒体中并抑制培养细胞的感染。我们在此建议使用MMTV进一步探测mA3和hA3蛋白的功能。我们将研究A3蛋白包装成病毒颗粒、限制逆转录病毒在体外和体内感染的机制、A3基因的多态性在影响病毒限制中的作用以及乳腺组织中A3的表达是否限制病毒的乳源性传播。作为这些研究的结果，我们将了解 A3 蛋白在外源病毒感染中发挥什么作用。这些研究将为了解该固有免疫因子家族如何抑制外源病毒（包括人类的 HIV-1 感染）对小鼠和其他物种的病毒感染提供基础。