Exploring the Role of Vif Antagonists in Preventing Sexual HIV Transmission

摘要 由于艾滋病的主要起因HIV-1疫苗的研制已被证明是困难的 随着流行病的蔓延，研究界已将一些重点转移到主题的发展上 杀微生物剂。由于阴道和直肠都是HIV-1进入的门户， 需要开发适合于保护这两个地点的杀菌剂。在这笔赠款中，我们将重点放在 以前从未探索过的预防艾滋病毒的新机制。在2002年，它是 发现HIV-1蛋白Vif的细胞靶点是APOBEC3G(A3G)。A3G是一种 AID/APOBEC家族，其特征是通过靶向脱氨基产生胞嘧啶 DNA中的尿嘧啶。APOBEC3G通过作用于病毒在逆转录病毒防御中发挥重要作用 逆转录本和调节许多关键的免疫反应。我们认为，A3G是 阴道和直肠中一种重要的逆转录病毒天然防御机制。通过使用 病毒蛋白Vif的抑制剂，Vif-APOBEC3G的相互作用被阻断，APOBEC3G被 不被蛋白质小体降解的。因此，致命的超突变被引入到 病毒的cdna转录本和HIV变得不能复制。 我们的拨款有四个具体目标： 具体目的1：探讨限制因子A3G在阴道粘膜组织中的作用 和直肠 具体目标2：检查RN18及其类似物在杀菌剂细胞中是否有效 HIV病毒体外传播模型及检测方法 具体目标3：阴道人源化BLT小鼠模型测试前景看好的Vif抑制剂 候选人 具体目标4：有希望的Vif抑制剂候选猕猴杀微生物剂模型试验 预计这些研究将确定A3G在阴道和直肠中的作用以及 病毒Vif蛋白的抑制剂是否可以防止艾滋病毒的性传播。

ABSTRACT Since it has proven difficult to develop a vaccine against HIV-1, the major cause of the AIDS pandemic, the research community has shifted some of its focus to the development of topical microbicides. Since both the vaginal and rectal tract are portals of HIV-1 entry, topical microbicides suitable to protect both sites need to be developed. In this grant, we focus on a novel mechanism that has not previously been explored for HIV prevention. In 2002, it was found that the cellular target of the HIV-1 protein Vif is APOBEC3G (A3G). A3G is an enzyme of the AID/APOBEC family, characterized by the targeted deamination of cytosine to generate uracil within DNA. APOBEC3G plays an important role in retroviral defense by acting on viral reverse transcripts and mediates numerous critical immune responses. We believe that A3G is an important innate retroviral defense mechanism in the vaginal and rectal tract. By using inhibitors of the viral protein Vif, the Vif-APOBEC3G interaction is blocked and APOBEC3G is not degraded by the proteosome. As a consequence, fatal hypermutations are introduced into the viral cDNA transcripts and HIV is rendered incompetent for replication. Our grant has four specific aims: Specific Aim 1: Explore the role of the restriction factor A3G in mucosal tissues of the vaginal and rectal tract Specific Aim 2: Examine whether RN18 and its analogs are active in microbicide cell-based assays and ex vivo explant HIV transmission models Specific Aim 3: Vaginal humanized BLT mouse model testing of promising Vif inhibitor candidates Specific Aim 4: Macaque microbicide model testing of promising Vif inhibitor candidates It is expected that these studies will define the role of A3G in the vaginal and rectal tract and whether inhibitors of the viral Vif protein can prevent sexual transmission of HIV.