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A Novel Mechanism of Restriction by an APOBEC3 Protein

APOBEC3 蛋白的新限制机制

基本信息

批准号：
8658651
负责人：
Edward Brice Stephens
金额：
$ 22.65万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8658651
关键词：
Alu Elements Amino Acid Substitution Amino Acids Anti-Retroviral Agents Antiviral Agents Apolipoproteins CD4 Positive T Lymphocytes Cells Cercopithecidae Chimeric Proteins Colobus Genus Cysteine Cytidine Deaminase DNA DNA Damage DNA Viruses DNA biosynthesis Data Deaminase Deamination Elements Epithelial Cells Family Future Genes Genome Glutamates Goals HIV HIV-1 Hela Cells Histidine Hominidae Human Human Activities Human Papillomavirus Human T-Cell Leukemia Viruses Immunity Infection Interferons Lymphocyte Macaca Macaca mulatta Messenger RNA Mice Minute Virus Molecular Parvovirus Phase Play Positioning Attribute Primates Production Property Protein Family Protein Inhibition Proteins Protons RNA Binding Reporting Research Personnel Retroelements Retrotransposition Retrotransposon Reverse Transcription Role SIV Subfamily lentivirinae Tertiary Protein Structure Transcript Viral Viral Genome Viral Physiology Viral Proteins Virus Virus Replication Zinc base cofactor design guereza inhibitor/antagonist innovation insertion/deletion mutation insight macrophage member monocyte mutant nonhuman primate novel polypeptide prevent public health relevance response simian human immunodeficiency virus tat Protein

项目摘要

PROJECT SUMMARY/ABSTRACT: The lentiviruses all encode for a Vif protein that has been shown to interact with members of the apolipoprotein mRNA-editing, catalytic polypeptide-like 3 (APOBEC3) superfamily of proteins. The APOBEC3 proteins are cytidine deaminases that are thought to play an important role in innate anti-viral immunity. Humans and macaques both encode for seven APOBEC3 genes (A3A, A3B, A3C, A3D, A3F, A3G, and A3H). The APOBEC3 proteins can be broadly divided into the single deaminase domain (A3A, A3C, and A3H) and double deaminase domain proteins (A3B, A3D, A3F, and A3G). Human A3A (hA3A) does not restrict the replication of HIV-1vif in 293 cells or HeLa cells but has recently been shown to inhibit replication of HIVvif in macrophage-derived macrophages (MDM). In contrast, rhA3A from rhesus macaques is capable of restricting both HIV-1 and SHIV (expressing the SIV Vif). We recently have assessed the ability of other non-human primate A3A proteins to restrict HIV-1 and HIV-1vif. We present preliminary data that the A3A protein from the Old World monkey, Colobus guereza (the mantled guereza, colA3A), not only inhibits the replication of HIV-1 and HIV-1vif but also inhibits virus production in producer cells. Our preliminary studies indicate that the colA3A inhibits by a novel post-entry mechanism and, but not after, proviral integration. In Specific Aim 1, we propose to determine the mechanism though which colA3A inhibits HIV-1 replication and assess the molecular determinants involved. In Specific Aim 2, we propose to determine whether expression of colA3A in human CD4+ T cells and macrophages can restrict HIV-1 in cells it naturally infects. The proposed studies will provide mechanistic insight into this novel mechanism of A3 protein inhibition of HIV-1, which could serve as a new anti-viral strategy against HIV-1.

项目总结/摘要：慢病毒都编码一种Vif蛋白，这种蛋白被证明与载脂蛋白的成员相互作用。 mRNA编辑，催化多肽样3（APOBEC 3）蛋白质超家族。APOBEC 3蛋白是胞苷脱氨酶被认为在先天性抗病毒免疫中起重要作用。人类和猕猴都编码7个APOBEC 3基因（A3 A、A3 B、A3 C、A3 D、A3 F、A3 G和A3 H）。的 APOBEC 3蛋白可以大致分为单脱氨酶结构域（A3 A、A3 C和A3 H）和双脱氨酶结构域（A3 A、A3 C和A3 H）。脱氨酶结构域蛋白（A3 B、A3 D、A3 F和A3 G）。人A3 A（hA 3A）不限制 HIV-1vif在293细胞或HeLa细胞中，但最近显示其抑制HIV的复制vif in 巨噬细胞衍生的巨噬细胞（MDM）。相比之下，来自恒河猴的rhA 3A能够限制 HIV-1和SHIV（表达SIV Vif）。我们最近评估了其他非人类生物限制HIV-1和HIV-1的灵长类A3 A蛋白vif.我们目前的初步数据表明，A3 A蛋白从旧大陆的猴子，Colobus guereza（mantled guereza，colA 3A），不仅抑制了 HIV-1和HIV-1而且抑制生产细胞中的病毒生产。我们的初步研究表明， colA 3A通过一种新的进入后机制抑制，而不是在前病毒整合之后。具体目标1、我们建议确定colA 3A抑制HIV-1复制的机制，并评估colA 3A抑制HIV-1复制的机制。分子决定簇参与。在具体目标2中，我们建议确定colA 3A在人类CD 4 + T细胞和巨噬细胞可以将HIV-1限制在其自然感染的细胞中。拟议的研究将提供了对A3蛋白抑制HIV-1的这种新机制的机制见解，这可以作为一种新的方法。针对HIV-1的新的抗病毒策略。