Chemical Contraceptive Control of Microbicides in the Female Reproductive Tract

化学避孕药对女性生殖道杀菌剂的控制

• 批准号: 9210054
• 负责人: Charles Robert Wira
• 金额: $ 63.39万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9210054
• 关键词: Adverse effects; Biological; Biological Availability; CD4 Positive T Lymphocytes; Cells; Chemicals; Clinical Trials; Coitus; Collaborations; Contraceptive Agents; Contraceptive Usage; Contraceptive methods; Development; Diphosphates; Dose; Effectiveness; Endocrine system; Enzymes; Epithelial Cells; Estradiol; Ethinyl Estradiol; Failure; Female; Fibroblasts; Formulation; Foundations; Gel; Goals; HIV; HIV Infections; HIV-1; Immune response; Immune system; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Innate Immune Response; Kinetics; Knowledge; Levonorgestrel; Ligands; Local Microbicides; Lymphoid Cell; Lymphoid Tissue; Measures; Medroxyprogesterone 17-Acetate; Metabolism; Norethindrone; Pharmaceutical Preparations; Phase; Phosphoric Monoester Hydrolases; Population Heterogeneity; Predisposition; Pregnancy; Prevention; Prodrugs; Progesterone; Regimen; Regulation; Reproductive Health; Research; Risk; Role; Source; Technology; Tenofovir; Testing; Tissues; Vagina; Woman; adenylate kinase; contraceptive microbicide; estrogenic; human female; improved; macrophage; men; microbicide; next generation; novel; prevent; public health relevance; reproductive tract; sex; sexual HIV transmission; uptake

 DESCRIPTION (provided by applicant): An urgent need exists to prevent the sexual transmission of HIV-1 to women. Worldwide, 70% of new cases are spread by sexual intercourse, with women more likely to be infected than men. Using a Multipurpose Prevention Technologies approach, we will test the overall hypothesis that some chemical contraceptives act directly on female reproductive tract (FRT) CD4+T cells and macrophages and indirectly through epithelial cells and fibroblasts in the absence or presence of inflammation to decrease availability of TFV diphosphate (TFV- DP), the biologically active form of TFV and TFV alafenamide (TAF), and thereby increase the risk of HIV infection in women. Since newer progestational chemical contraceptives (LNG: Levonorgestrel and NET: norethisterone) have fewer side effects than medroxyprogesterone acetate (MPA), central to this proposal is the comparison of MPA to LNG and NET, and their effects on both TFV and TAF, the likely next generation microbicide that better targets lymphoid tissues and cells through enhanced uptake and subsequent conversion to TFV. This proposal has 3 Aims that test the following hypotheses: Aim 1. Chemical contraceptives act directly to alter TFV-DP intracellular levels in HIV-target cells in human FRT tissues in ways that compromise microbicide protection against HIV infection. Aim 2. Chemical contraceptives regulate TFV-DP concentrations in HIV-target cells through mechanisms that alter the enzymes necessary for the formation and/or degradation of TFV-DP. Aim 3. Inflammatory factors (PRR Ligands) and chemical contraceptives alter intracellular availability of TFV and TAF and compromise innate immune responses by HIV-target cells from the FRT. This study is unique in that it integrates our understanding of the endocrine and immune systems in the human FRT, as it relates directly to intracellular TFV-DP concentrations in the very cells most likely to be infected by HIV. Our goal is to determine how the next generation of chemical contraceptives (LNG or NET) influence microbicide (TFV and TAF) availability in FRT HIV-target cells and how inflammatory factors compromise these effects. Building on our past research, we expect that these studies will demonstrate that some chemical contraceptive/microbicide combinations, will compromise microbicide efficacy and protection against HIV infection especially in the presence of inflammatory mediators. These studies will provide a foundation of information essential for the development of the next generation of combined chemical contraceptives and microbicides needed to provide both contraception and improved protection against HIV infection.

 描述（由适用提供）：迫切需要防止HIV-1向女性进行性传播。在全球范围内，有70％的新病例是通过性交传播的，女性比男性更有可能被感染。使用多功能预防技术方法，我们将测试总体假设，即某些化学避孕药直接作用于女性生殖道（FRT）CD4+T细胞和巨噬细胞和巨噬细胞以及通过上皮细胞和成纤维细胞间接作用，并在不存在炎症的情况下进行炎症，以降低TFV Diphostry and tfv-tfv-dpfv-dpv-dp dp dp dp dp dp dp。 Alafenamide（TAF），从而增加女性艾滋病毒感染的风险。由于较新的鸡蛋化学避孕药（LNG：左甲状腺肿和网络：北源）的副作用少于乙酸酯（MPA）（MPA），因此该建议的核心是MPA与LNG和NG的比较，是MPA与LNG和NET的比较，其对下一代的细胞和细胞的影响，可能会增强型号的细胞和较大的细胞。 TFV。该提议的3个目的是检验以下假设：目标1。化学避孕药直接起作用，以改变人FRT组织中HIV目标细胞中的TFV-DP细胞内水平，以损害微生物保护的方式。2。化学避孕药以通过机械主义的机制来调节HIV-DP的化学避孕药，以改变endf and的机制，以适应不能进行不能或der的形式。 AIM 3。炎症因子（PRR配体）和化学避孕药改变了TFV和TAF的细胞内可用性，并损害了来自FRT的HIV靶标细胞的先天免疫反应。这项研究的独特之处在于，它整合了人类FRT中内分泌和免疫系统的理解，因为它直接与最有可能被HIV感染的细胞内细胞内TFV-DP浓度有关。我们的目标是确定下一代化学避孕药（LNG或NET）如何影响FRT HIV靶细胞中的菌心（TFV和TAF）的可用性，以及炎症因子如何损害这些影响。在我们过去的研究的基础上，我们预计这些研究将表明某些化学避孕/杀菌剂组合将损害杀菌剂的效率和保护艾滋病毒感染的效率，尤其是在存在炎症介质的情况下。这些研究将为开发下一代化学避孕剂和所需的杀菌剂提供避孕剂和改善对HIV感染的保护所需的杀菌剂所必需的信息基础。