Regulation and Action of APOBEC3G

APOBEC3G的监管和行动

• 批准号: 7414017
• 负责人: Warner C. Greene
• 金额: $ 52.12万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7414017
• 关键词: 5-bromo-4-chloro-3-indolyl beta-galactoside; Adverse effects; Affect; Amino Acids; Anti-Retroviral Agents; Antiviral Agents; Binding; Biological; Biological Assay; Biology; CD4 Positive T Lymphocytes; Catalytic Domain; Cell physiology; Cells; Clinical; Complex; Cytidine; Cytidine Deaminase; DNA; Deamination; Deoxycytidine; Detection; Development; Disruption; Dissection; Drug Delivery Systems; ES Cell Line; Enzymes; Eukaryotic Cell; Exhibits; Family member; Fire - disasters; Galactosidase; Gene Family; Genes; Genetic Transcription; Genome; Growth; HIV; HIV Budding; HIV Infections; HIV drug resistance; Human T-lymphotropic virus 1; Immune; Integration Host Factors; Interleukin-2; Introns; Laboratories; Malignant Neoplasms; Mammalian Cell; Manuscripts; Mediating; Messenger RNA; Mitogens; Molecular Weight; Monoclonal Antibody HuM291; Muromonab-CD3; Mus; Mutate; Mutation; Ovary; Pancreatic ribonuclease; Paper; Phytohemagglutinins; Preparation; Production; Proteins; RNA; RNA Editing; Range; Recruitment Activity; Regulation; Reporter Genes; Research Personnel; Rest; Retroviridae; Reverse Transcription; Ribonucleoproteins; SIV; Scientist; Seminal; Small Interfering RNA; T-Lymphocyte; Testing; Testis; Time; Tissue Stains; Tissues; Transcript; Transgenic Mice; Viral; Virion; Virus; acrosome stabilizing factor; analog; apoB mRNA editing catalytic subunit; apolipoprotein B mRNA editing enzyme; base; blocking factor; cytokine; fascinate; in vivo; insight; interest; member; monocyte; multicatalytic endopeptidase complex; mutant; novel; novel therapeutics; polypeptide; programs; receptor; reproductive; research study; vector; vif Gene Products; viral DNA; viral RNA

DESCRIPTION (provided by applicant): Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-1 like 3G (APOBEC3G, A3G) corresponds to a host-derived cytidine deaminase that displays potent anti-retroviral activity. When incorporated into budding HIV virions, the A3G enzyme massively mutates nascent HIV DNA produced during reverse transcription in the next target cell thereby halting HIV growth. HIV counters these effects of A3G through its Vif gene product, which promotes accelerated proteasome-mediated degradation and partially impaired de novo synthesis of A3G. The intracellular depletion of A3G makes the antiviral enzyme unavailable for incorporation into progeny virions. Our recent studies have unveiled a second antiviral action of A3G operating in resting CD4 T-cells. In these T-lymphocytes, cellular A3G functions as a highly active post-entry restriction factor blocking the growth of both wild type and deltaVif forms of HIV. Whether this "Vif-resistant" anti-HIV defense mediated by A3G involves cytidine deamination or a different mechanism is currently unknown. Further, the mechanism by which this post-entry restricting function of A3G is forfeited when T-cells are activated remains incompletely understood. Similarly, little is known about how host cells safeguard their own DNA from the mutagenic effects of A3G. Finally, it remains unknown whether A3G exerts other key functions beyond these antiviral effects. In Specific Aim 1, experiments will be performed to decipher how A3G and the closely related A3F and A3B antiviral enzymes are regulated in cells. In Specific Aim 2, the mechanism of A3G action as a post-entry restriction factor in resting CD4 T-cells, the range of viruses affected by this restriction, and potential similar functions of A3F will be delineated. Finally, in Specific Aim 3, studies will be conducted to assess whether A3G mediates important non-antiviral functions in mammalian cells. These experiments will involve the preparation and analysis of mice lacking the functional analogue of the A3G gene. Together, this program of proposed experimentation promises to enrich our understanding of the biology of A3G as well as the related A3F and A3B enzymes. With such understanding, new therapeutic strategies for inhibiting HIV growth could emerge.

描述（由申请人提供）：载脂蛋白B mRNA编辑酶，催化多肽-1（如3G）（Apobec3g，A3G）对应于宿主衍生的胞苷脱氨酸酶，表现出有效的抗逆转录病毒活性。当掺入萌芽的HIV病毒体中时，A3G酶在下一个靶细胞中逆转录过程中产生的新生HIV DNA大体突变，从而停止HIV生长。 HIV通过其VIF基因产物来抵消A3G的这些影响，从而促进了蛋白酶体介导的降解，并部分受损的A3G合成。 A3G的细胞内耗竭使抗病毒酶无法掺入后代病毒体中。我们最近的研究揭示了在静止的CD4 T细胞中运行A3G的第二种抗病毒作用。在这些T淋巴细胞中，细胞A3G充当了高度活跃的进入后限制因子，阻断了HIV的野生型和Deltavif形式的生长。目前尚不清楚这种“耐VIF”抗HIV防御涉及胞苷脱氨酸或其他机制。此外，当T细胞被激活时，该限制后A3G的限制功能的机制仍未完全理解。同样，关于宿主细胞如何保护自己的DNA免受A3G的诱变作用，知之甚少。最后，尚不清楚A3G是否在这些抗病毒作用之外发挥了其他关键功能。在特定的目标1中，将进行实验，以破译A3G和密切相关的A3F和A3B抗病毒酶如何在细胞中调节。在特定的目标2中，A3G作用作为静止CD4 T细胞的进入后限制因素的机制，受该限制影响的病毒范围以及A3F的潜在类似功能将被描述。最后，在特定目标3中，将进行研究以评估A3G是否介导哺乳动物细胞中重要的非抗病毒功能。这些实验将涉及缺乏A3G基因功能类似物的小鼠的制备和分析。共同，该提出的实验计划有望丰富我们对A3G以及相关A3F和A3B酶的生物学的理解。有了这样的理解，可能会出现抑制艾滋病毒增长的新治疗策略。