Actions of Vif and APOBEC3 proteins in HIV-1 Replication

描述(申请人提供)：人类免疫缺陷病毒1型(HIV-1)感染CD4阳性T细胞和单核/巨噬细胞，导致人类获得性免疫缺陷综合征(AIDS)。在这项申请中提出的研究重点是抵抗艾滋病毒-1感染的细胞因子，这些因子在艾滋病毒进入细胞后立即被激活。这些蛋白是细胞胞苷脱氨酶(APOBEC蛋白)，在基因组靶点上将胞嘧啶转化为尿嘧啶，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，从而阻止它们的复制。HIV-1(和其他灵长类慢病毒)通过产生病毒感染性因子Vif绕过了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，这些相互作用为开发APOBEC3蛋白作为抗HIV治疗的新工具提供了一个独特和新颖的机会。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。这项建议将针对三个具体目标：(1)研究这种抗病毒天然免疫的分子结构，并确定更多的APOBEC3家族成员；(2)研究APOBEC3蛋白的酶复合体，并确定可能的编辑小体中存在的细胞辅助因子；(3)确定Vif通过结合和破坏APOBEC3来破坏这种固有细胞内免疫的确切机制。这个项目将导致对这种先天免疫系统的结构的定义，并将导致对感染过程中的抗病毒机制的充分理解。重要的是，我们将确定VIF篡改的分子决定簇(S)，以抵消这种免疫。将发现新的治疗靶点来帮助我们修复这种免疫的脆弱方面，以便它能够在艾滋病毒感染期间发挥结构性作用。这些发现可能会为艾滋病毒感染的治疗提供一种更有效的方式，与其他化疗和疫苗一起使用。

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.