Exploring the Role of Vif Antagonists in Preventing Sexual HIV Transmission

描述（由申请人提供）：由于事实证明很难研制出针对艾滋病毒-1（艾滋病大流行的主要原因）的疫苗，研究界已将部分重点转移到局部杀微生物剂的开发上。由于阴道和直肠都是HIV-1进入的入口，因此需要开发适合保护这两个部位的局部杀微生物剂。在这项资助中，我们专注于一种以前从未探索过的预防艾滋病毒的新机制。2002年，发现HIV-1蛋白Vif的细胞靶点是APOBEC3G （A3G）。A3G是AID/APOBEC家族的一种酶，其特征是在DNA内靶向胞嘧啶脱胺生成尿嘧啶。APOBEC3G通过作用于病毒逆转录物在逆转录病毒防御中发挥重要作用，并介导许多关键的免疫反应。我们认为A3G是阴道和直肠道中重要的先天逆转录病毒防御机制。通过使用病毒蛋白Vif抑制剂，Vif-APOBEC3G相互作用被阻断，APOBEC3G不会被蛋白体降解。结果，致命的超突变被引入到病毒cDNA转录本中，HIV无法复制。我们的资助有四个特定目标：特定目标1：探索限制因子A3G在阴道和直肠粘膜组织中的作用特定目标2：研究RN18及其类似物是否在基于杀微生物剂细胞的检测和体外外植体HIV传播模型中具有活性特定目标3：阴道人源化BLT小鼠模型测试有希望的Vif抑制剂候选物特定目标4：预期这些研究将明确A3G在阴道和直肠中的作用，以及病毒Vif蛋白抑制剂是否可以预防HIV的性传播。

DESCRIPTION (provided by applicant): 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.