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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的由于事实证明很难开发针对HIV-1的疫苗，这是艾滋病的主要原因大流行，研究界将其一些重点转移到了主题的发展上微生物。由于阴道和直肠道是HIV-1进入的门户，因此需要开发适合保护两个地点的菌心。在这笔赠款中，我们专注于以前尚未探讨HIV预防的新型机制。在2002年，发现HIV-1蛋白VIF的细胞靶标为Apobec3g（A3G）。 A3G是 AID/APOBEC家族，其特征是细胞儿的靶向脱氨基 DNA内的尿嘧啶。 APOBEC3G通过对病毒作用在逆转录病毒防御中起重要作用逆转录并介导许多关键的免疫反应。我们相信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的抑制剂，VIF-APOBEC3G相互作用被阻断，APOBEC3G为蛋白体不会降解。结果，致命的超血被引入病毒cDNA转录本和HIV具有无能复制。我们的赠款有四个具体的目标：特定目标1：探索限制因子A3G在阴道粘膜组织中的作用和直肠道特定目标2：检查RN18及其类似物是否在基于菌心细胞中活跃测定和Ex Vivo Epplant HIV传播模型特定目的3：有希望的VIF抑制剂的阴道人性化BLT小鼠模型测试候选人特定目的4：有希望的VIF抑制剂候选者的猕猴杀菌模型测试预计这些研究将定义A3G在阴道和直肠道中的作用，以及病毒VIF蛋白的抑制剂是否可以防止HIV的性传播。