Mechanism of APOBEC3-Mediated Innate Immunity to HIV-1

描述（由申请人提供）：逆转录病毒研究的最新进展，即APOBEC 3（A3）亚家族蛋白质的成员有效阻断逆转录病毒的复制，为人类免疫缺陷病毒1型（HIV-1）感染的抗逆转录病毒疗法的开发开辟了新的途径。该亚家族包括A3 A、A3 B、A3 C、A3 DE、A3 F、A3 G和A3 H，它们属于胞苷脱氨酶家族。它们在病毒组装过程中掺入病毒颗粒中，并破坏病毒逆转录以抑制病毒复制。HIV-1产生一种病毒感染因子Vif，作为这些蛋白质和Cullin 5-基E3泛素连接酶之间的桥梁，通过蛋白酶体途径破坏大多数A3蛋白。虽然这些发现令人兴奋，但该领域希望进一步了解这种A3介导的免疫性如何阻止逆转录病毒感染以及为什么它对Vif如此脆弱。我们的长期目标是了解如何有效地靶向有助于逆转录病毒感染的先天免疫的宿主因素，以改善HIV-1感染的治疗。本研究的目的是进一步研究A3蛋白的抗逆转录病毒机制及其在Vif作用下的蛋白酶体降解过程。我们的理论基础是，如果我们能找到一种表达A3蛋白的策略，使其对Vif不敏感，就可以开发一种新的抗HIV-1疗法。我们提出了以下三个具体目标：1）研究人A3 H的抗逆转录病毒活性; 2）研究A3 G的抗逆转录病毒辅助因子; 3）研究A3 G的泛素非依赖性蛋白酶体降解。该项目的创新之处在于，它提供了一个通过了解A3 H的功能来充分定义A3介导的抗逆转录病毒免疫的结构的机会。它将通过精确定义与A3抗逆转录病毒活性及其在蛋白酶体中降解相关的机制来显着推进我们的知识。在这个项目完成后，我们希望我们不仅能够解决这些基本问题，而且还能够证明利用这种免疫力来对抗HIV-1感染的可行性。这些发现将有助于与其他化疗和疫苗结合使用更有效的治疗艾滋病毒感染的方式。

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.