Exploring the Role of Vif Antagonists in Preventing Sexual HIV Transmission

探索 Vif 拮抗剂在预防 HIV 性传播中的作用

• 批准号: 8665373
• 负责人: Mario Stevenson
• 金额: $ 41.34万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8665373
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Address; Africa South of the Sahara; Animals; Anti-Retroviral Agents; Asia; Beer; Biological Assay; Cells; Cellulose; Cervical; Charge; Chemicals; Coitus; Collaborations; Colorectal; Communities; Complementary DNA; Cytidine Deaminase; Cytosine; DNA; Data; Deamination; Defense Mechanisms; Dendritic Cells; Descending colon; Development; Drug Combinations; Drug Formulations; Drug resistance; Endocervix; Enhancers; Enzymes; Exocervix; Exposure to; FDA approved; Family; Genital system; Goals; Grant; HIV; HIV-1; Health; Human; Hydroxyl Radical; Immune response; Immunohistochemistry; Infection; Lactobacillus; Life Cycle Stages; Local Microbicides; Lymphocyte; Macaca; Macaca mulatta; Mediating; Modeling; Monkeys; Mucous Membrane; Mus; North Carolina; Penetration; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Placebos; Play; Premenopause; Prevention; Primates; Proteasome Inhibitor; Protein Binding; Proteins; Publishing; RNA; Rectum; Research; Research Design; Research Methodology; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; SIV; Seminal Plasma; Seminal fluid; Sexual Partners; Sexual Transmission; Site; Slide; Staging; Staining method; Stains; System; Tenofovir; Testing; Time; Tissues; Toxic effect; Toxicity Tests; Transcript; Ubiquitin; Unsafe Sex; Uracil; Vagina; Viral; Viral Proteins; Virus; Virus Diseases; Virus Inhibitors; Vulva; Woman; analog; base; cellular targeting; condoms; design; fitness; functional restoration; human female; human tissue; in vitro Assay; inhibitor/antagonist; macrophage; microbicide; mouse model; multicatalytic endopeptidase complex; mutant; non-drug; novel; pandemic disease; pinacolyl methylphosphonic acid; prevent; prototype; rectal; rectum/anus; reproductive; simian human immunodeficiency virus; small molecule; transmission process; uptake; vaccine development; vaginal fluid; vif Gene Products; virus culture

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.

摘要 由于已经证明很难开发出针对艾滋病主要原因HIV-1的疫苗， 大流行，研究界已将其重点转移到发展专题 杀菌剂。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部位的杀微生物剂。在这份补助金中，我们专注于 以前尚未探索过的预防艾滋病毒的新机制。2002年被 发现HIV-1蛋白Vif的细胞靶点是APOBEC 3G（A3 G）。A3 G是一种酶， AID/APOBEC家族，其特征在于胞嘧啶的靶向脱氨基以产生 DNA中的尿嘧啶。APOBEC 3G在逆转录病毒防御中发挥重要作用，作用于病毒 逆转录并介导许多关键的免疫反应。我们认为A3 G是 一种重要的先天性逆转录病毒防御机制在阴道和直肠道。通过使用 当使用病毒蛋白Vif的抑制剂时，Vif-APOBEC 3G相互作用被阻断，APOBEC 3G被抑制。 不被蛋白体降解。因此，致命的超突变被引入到 病毒的cDNA转录物和HIV不能复制。 我们的赠款有四个具体目标： 具体目的1：探讨限制性因子A3 G在阴道粘膜组织中的作用 和直肠道 具体目标2：检查RN 18及其类似物是否在基于细胞的杀微生物剂中具有活性 测定和离体外植体HIV传播模型 具体目的3：有希望的Vif抑制剂的阴道人源化BLT小鼠模型测试 候选人 具体目标4：有希望的Vif抑制剂候选物的猕猴杀微生物剂模型测试 预计这些研究将确定A3 G在阴道和直肠中的作用， 病毒Vif蛋白的抑制剂是否可以预防HIV的性传播。