Mechanism of APOBEC3-Mediated Innate Immunity to HIV-1

APOBEC3介导的HIV-1先天免疫机制

基本信息

批准号：
8096732
负责人：
YONG-HUI ZHENG
金额：
$ 10.38万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8096732
关键词：
Adaptor Signaling Protein Address American Society of Hematology Anti-Retroviral Agents Architecture Clinical Collaborations Cullin 5 Protein Cytidine Deaminase Development Family Genetic Polymorphism Goals HIV HIV Infections HIV-1 Human Human Activities Immunity Impairment Infection Integration Host Factors Knowledge Lead Libraries Manuscripts Mediating Modality Mutation Natural Immunity Paper Pathogenesis Pathway interactions Postdoctoral Fellow Process Proteins Publishing Research Research Personnel Retroviridae Role Training Ubiquitin Vaccines Viral Viral Reverse Transcription Work acrosome stabilizing factor antiretroviral therapy base chemotherapy cofactor combat expectation genetic analysis improved in vivo inhibitor/antagonist innovation mRNA Expression member multicatalytic endopeptidase complex novel novel therapeutics particle programs ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Recent advances on retroviral research that members of APOBEC3 (A3) subfamily proteins potently blocks replication of retroviruses have opened a new avenue for the development of antiretroviral therapy for human immunodeficiency virus type 1 (HIV-1) infection. This subfamily includes A3A, A3B, A3C, A3DE, A3F, A3G and A3H, which belong to the cytidine deaminase family. They are incorporated into viral particles during viral assembly and disrupt viral reverse transcription to inhibit viral replication. As a counteraction, HIV-1 produces a viral infectivity factor, Vif, to destruct most of the A3 proteins via the proteasomal pathway by serving as a bridge between these proteins and a Cullin 5-based E3 ubiquitin ligase. Although these discoveries are exciting, the field desires for further understanding of how this A3-mediated immunity blocks retroviral infection and why it is so vulnerable to Vif. Our long-term goal is to understand how host factors that contribute to the innate immunity to retroviral infection can be effectively targeted for improved treatment of HIV-1 infection. Our objective in this proposal is to further study the antiretroviral mechanism of A3 protein and the process of their proteasomal degradation triggered by Vif. Our rationale is that a new anti-HIV-1 therapy could be developed if we can find a strategy to express A3 proteins that become insensitive to Vif. We propose the following three specific aims: 1) To study the antiretroviral activity of human A3H; 2) To study the antiretroviral cofactor for A3G; 3) To study the ubiquitin-independent proteasomal degradation of A3G. This project is innovative in that, it offers an opportunity to fully define the architecture of A3-mediated antiretroviral immunity by understanding the function of A3H. It will significantly advance our knowledge by precisely defining the mechanisms related to A3 antiretroviral activity and their degradation in proteasomes. At the completion of this project, it is our expectation that we will be able to not only address these fundamental issues, but also demonstrate the feasibility to employ this immunity to combat HIV-1 infection. Such findings will contribute to 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）：逆转录病毒研究的最新进展表明 APOBEC3 (A3) 亚家族蛋白的成员可有效阻断逆转录病毒的复制，这为开发人类免疫缺陷病毒 1 型 (HIV-1) 感染的抗逆转录病毒疗法开辟了新途径。该亚家族包括A3A、A3B、A3C、A3DE、A3F、A3G和A3H，属于胞苷脱氨酶家族。它们在病毒组装过程中被掺入病毒颗粒中，并破坏病毒逆转录以抑制病毒复制。作为一种对抗作用，HIV-1 会产生一种病毒感染因子 Vif，通过蛋白酶体途径破坏大部分 A3 蛋白，充当这些蛋白与基于 Cullin 5 的 E3 泛素连接酶之间的桥梁。尽管这些发现令人兴奋，但该领域希望进一步了解这种 A3 介导的免疫如何阻止逆转录病毒感染以及为什么它如此容易受到 Vif 的影响。我们的长期目标是了解如何有效地针对有助于逆转录病毒感染先天免疫的宿主因素来改善 HIV-1 感染的治疗。我们本提案的目的是进一步研究A3蛋白的抗逆转录病毒机制以及Vif引发的蛋白酶体降解过程。我们的理由是，如果我们能找到一种策略来表达对 Vif 不敏感的 A3 蛋白，就可以开发出一种新的抗 HIV-1 疗法。我们提出以下三个具体目标：1）研究人A3H的抗逆转录病毒活性； 2）研究A3G的抗逆转录病毒辅助因子； 3) 研究A3G的不依赖泛素的蛋白酶体降解。该项目的创新之处在于，它提供了一个机会，通过了解 A3H 的功能来全面定义 A3 介导的抗逆转录病毒免疫的架构。通过精确定义与 A3 抗逆转录病毒活性及其在蛋白酶体中降解相关的机制，它将显着增进我们的知识。在这个项目完成后，我们期望我们不仅能够解决这些基本问题，而且能够证明利用这种免疫力来对抗 HIV-1 感染的可行性。这些发现将有助于找到一种与其他化疗和疫苗联合使用的更有效的艾滋病毒感染治疗方法。