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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：
8780591
负责人：
Edward Brice Stephens
金额：
$ 18.88万
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 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8780591
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

DESCRIPTION (provided by applicant): 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-1 vif in 293 cells or HeLa cells but has recently been shown to inhibit replication of HIV vif 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-1 vif. 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-1 vif 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.

描述（由申请人提供）：慢病毒均编码Vif蛋白，已显示Vif蛋白与载脂蛋白mRNA编辑、催化多肽样3（APOBEC 3）蛋白超家族成员相互作用。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）。APOBEC 3蛋白质可大致分为单脱氨酶结构域（A3 A、A3 C和A3 H）和双脱氨酶结构域蛋白质（A3 B、A3 D、A3 F和A3 G）。人A3 A（hA 3A）不限制HIV-1 vif在293细胞或HeLa细胞中的复制，但最近已显示出抑制HIV vif在巨噬细胞衍生的巨噬细胞（MDM）中的复制。相反，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灵长类动物A3 A蛋白限制HIV-1和HIV-1 vif的能力。我们目前的初步数据表明，A3 A蛋白从旧大陆猴，疣猴（mantled guereza，colA 3A），不仅抑制HIV-1和HIV-1病毒的复制，但也抑制生产细胞中的病毒生产。我们的初步研究表明，colA 3A抑制一种新的后进入机制，但不是后，前病毒整合。在具体目标1中，我们建议确定colA 3A抑制HIV-1复制的机制，并评估所涉及的分子决定因素。在具体目标2中，我们建议确定colA 3A在人CD 4 + T细胞和巨噬细胞中的表达是否可以限制HIV-1在其自然感染的细胞中的表达。这些研究将为A3蛋白抑制HIV-1的新机制提供机制上的见解，这可能成为一种新的抗HIV-1的抗病毒策略。