Actions of Vif and APOBEC3 proteins in HIV-1 Replication

描述（由申请人提供）：人类免疫缺陷病毒1型（HIV-1）感染cd4阳性T细胞和单核/巨噬细胞并引起人类获得性免疫缺陷综合征（AIDS）。在本应用程序中提出的研究重点是抗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。这些蛋白是细胞胞苷脱氨酶（称为APOBEC蛋白），它们在基因组靶点上将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，从而阻断其复制。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，开发出成功的治疗HIV-1的方法。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，并确定额外的APOBEC3家族成员；(2)研究APOBEC3蛋白的酶复合物，并确定在假定的编辑体中存在的细胞辅助因子；(3)明确Vif通过结合和破坏APOBEC3s破坏这种先天细胞内免疫的确切机制。这个项目将导致这种先天免疫系统的结构的定义，也将导致在感染期间的抗病毒机制的充分理解。重要的是，我们将确定被Vif篡夺的分子决定因素来抵消这种免疫。新的治疗靶点将被发现，以帮助我们修复这种免疫的脆弱方面，使其在艾滋病毒感染期间能够组成性地发挥作用。这些发现可能为治疗艾滋病毒感染提供一种更有效的方式，可与其他化疗和疫苗结合使用。

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.