Mechanism of APOBEC3-Mediated Innate Immunity to HIV-1

APOBEC3(A3)亚家族蛋白的逆转录病毒研究进展 阻断逆转录病毒的复制为抗逆转录病毒疗法的发展开辟了一条新的途径 人类免疫缺陷病毒1型(HIV-1)感染。此子家族包括ASA、A3B、A3C、A3DE、 ASF、A3G和ASH，属于胞苷脱氨酶家族。它们被合并到病毒颗粒中 在病毒组装过程中，并扰乱病毒反转录，以抑制病毒复制。作为反击， HIV-1产生一种病毒感染性因子Vif，通过蛋白酶体途径破坏大部分A3蛋白 通过充当这些蛋白质和基于cullin 5的E3泛素连接酶之间的桥梁。尽管这些 发现是令人兴奋的，该领域渴望进一步了解这种AS介导的免疫是如何阻止的 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宿主因素是如何 有助于对逆转录病毒感染的先天免疫的人可以有效地被靶向地改进治疗 HIV-1感染的可能性。本研究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。我们的理由是一种新的抗HIV-1 如果我们能找到一种策略来表达对Vif不敏感的A3蛋白，就可以开发治疗方法。 我们提出了以下三个具体目标：1)研究人ASH的抗逆转录病毒活性；2)研究人ASH的抗逆转录病毒活性 研究A3G的抗逆转录病毒辅助因子；3)研究A3G泛素非依赖性蛋白酶体的降解 A3G。这个项目的创新之处在于，它提供了一个充分定义已更新的体系结构的机会 通过了解ASH的功能获得抗逆转录病毒免疫。它将极大地促进我们的知识，通过 精确定义与蛋白酶体中A3抗逆转录病毒活性及其降解相关的机制。 在这个项目完成后，我们期望我们不仅能够解决这些问题 这不仅表明了基本问题，而且也证明了利用这种免疫来抗击艾滋病毒-1感染的可行性。 这些发现将有助于建立一种更有效的艾滋病毒感染治疗方法，用于 与其他化疗和疫苗联合使用。

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 ASA,A3B, A3C, A3DE, ASF, A3G and ASH, 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 AS-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 ASH; 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 ofAS-nnediated antiretroviral immunity by understanding the function of ASH. 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.