Actions of Vif and APOBEC3 proteins in HIV-1 Replication

Vif 和 APOBEC3 蛋白在 HIV-1 复制中的作用

基本信息

批准号：
7919639
负责人：
YONG-HUI ZHENG
金额：
$ 14.61万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-17 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7919639
关键词：
Acquired Immunodeficiency Syndrome Address Anti-Retroviral Agents Antiviral Agents Architecture Binding Biochemical Cells Complementary DNA Complex Cytidine Deaminase Cytosine Data F Box Domain Family member Genomics HIV HIV Infections HIV-1 Host Defense Host Defense Mechanism Human Immune Immune response Immune system Immunity Infection Integration Host Factors Lead Modality Molecular Molecular Structure Natural Immunity Play Primate Lentiviruses Production Proteins Research Retroviridae Role SIV Structure Subfamily lentivirinae Substrate Specificity System T-Lymphocyte Techniques Testing Therapeutic Time Ubiquitin Uracil Vaccines Viral Viral Genome Viral Physiology Viral Proteins Virus Diseases base chemotherapy cofactor design intermolecular interaction macrophage monocyte multicatalytic endopeptidase complex new therapeutic target novel particle protein degradation protein metabolism repaired therapeutic development tool ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Human Immunodeficiency Virus Type 1 (HIV-1) infects CD4-positive T cells and monocytes/macrophages and cause Acquired Immune Deficiency Syndrome (AIDS) in humans. Research proposed in this application is focusing on the cellular factors that resist HIV-1 infection that are activated immediately after HIV enters cells. These proteins are cellular cytidine deaminases (called APOBEC proteins) that convert cytosines to uracils on genomic targets and play important roles in protein metabolism and immune responses. The critical factor for our study is the recent finding that APOBEC3 proteins modify HIV-1 viral genomes and thus block their replication. This potent protective mechanism is circumvented by HIV-1 (and other primate lentiviruses) by their production of a viral infectivity factor, Vif. Vif renders the APOBEC3 proteins inactive and thus allows viral infection. These exciting discoveries have uncovered a fierce battlefield between retroviruses and intracellular immune networks. At the same time, these interactions provide for a unique and novel opportunity to exploit APOBEC3 proteins as new tools for anti-HIV therapeutics. Our long-term objective is to develop successful therapeutic treatments for HIV-1 by overcoming the vulnerability of this innate immunity to viral protein Vif. This proposal will address three specific aims: (1) To study the molecular structure of this antiviral innate immunity and identify additional APOBEC3 family members; (2) To study the enzymatic complex of APOBEC3 proteins and determine the cellular cofactors present in the putative editosome; (3) To define the precise mechanism by which Vif disrupts this innate intracellular immunity by binding to and destroying APOBEC3s. This project will lead to a definition of the architecture of this innate immune system, and will also lead to a full understanding of the antiviral mechanism during infection. Importantly, we will identify the molecular determinant(s) usurped by Vif to counteract this immunity. New therapeutic targets will be discovered to help us repair the vulnerable aspect of this immunity so it can constitutively function during HIV infection. Such findings may provide a more effective modality for the treatment of HIV infection to be used in conjunction with other chemotherapy and vaccines.

描述（由申请人提供）：1 型人类免疫缺陷病毒 (HIV-1) 感染 CD4 阳性 T 细胞和单核细胞/巨噬细胞，并导致人类获得性免疫缺陷综合症 (AIDS)。本申请中提出的研究重点是抵抗 HIV-1 感染的细胞因子，这些因子在 HIV 进入细胞后立即被激活。这些蛋白质是细胞胞苷脱氨酶（称为 APOBEC 蛋白质），可将基因组靶标上的胞嘧啶转化为尿嘧啶，并在蛋白质代谢和免疫反应中发挥重要作用。我们研究的关键因素是最近发现 APOBEC3 蛋白修饰 HIV-1 病毒基因组，从而阻止其复制。 HIV-1（和其他灵长类慢病毒）通过产生病毒感染因子 Vif 来规避这种有效的保护机制。 Vif 使 APOBEC3 蛋白失活，从而允许病毒感染。这些令人兴奋的发现揭示了逆转录病毒和细胞内免疫网络之间的激烈战场。同时，这些相互作用为利用 APOBEC3 蛋白作为抗 HIV 治疗的新工具提供了独特而新颖的机会。我们的长期目标是通过克服这种先天免疫对病毒蛋白 Vif 的脆弱性，开发成功的 HIV-1 治疗方法。该提案将解决三个具体目标：（1）研究这种抗病毒先天免疫的分子结构并鉴定其他 APOBEC3 家族成员； (2) 研究APOBEC3蛋白的酶复合物并确定假定的编辑体中存在的细胞辅因子； (3) 明确 Vif 通过结合并破坏 APOBEC3 来破坏这种先天细胞内免疫的精确机制。该项目将导致对这种先天免疫系统的架构的定义，并将导致对感染过程中抗病毒机制的全面了解。重要的是，我们将确定 Vif 篡夺的分子决定簇来抵消这种免疫力。我们将发现新的治疗靶点来帮助我们修复这种免疫力的脆弱方面，使其能够在艾滋病毒感染期间发挥基本功能。这些发现可能为治疗艾滋病毒感染提供一种更有效的方法，与其他化疗和疫苗联合使用。