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（由申请人提供）：迫切需要预防 HIV-1 向女性的性传播。在世界范围内，70% 的新病例是通过性交传播的，女性比男性更容易被感染。随着技术的进步，我们将测试总体假设，即一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，并在不存在或存在炎症的情况下通过上皮细胞和成纤维细胞间接作用减少 TFV 二磷酸盐 (TFV-DP)、TFV 和 TFV 艾拉酚胺 (TAF) 的生物活性形式的可用性，从而增加女性感染 HIV 的风险，因为新型孕期化学避孕药（LNG：左炔诺孕酮和 NET：炔诺酮）。比醋酸甲羟孕酮 (MPA) 副作用更少，该提案的核心是将 MPA 与 LNG 和 NET 进行比较，以及它们对 TFV 和 TAF 的影响，TFV 和 TAF 可能是下一代杀菌剂，通过增强摄取和随后转化为 TFV 更好地靶向淋巴组织和细胞。该提案有 3 个目标来检验以下假设： 目标 1. 化学避孕药直接作用于改变。人类 FRT 组织中 HIV 靶细胞中 TFV-DP 的细胞内水平会损害杀菌剂对 HIV 感染的保护作用。 目标 2.化学避孕药调节 HIV 靶标中的 TFV-DP 浓度。目标 3：炎症因子（PRR 配体）和化学避孕药改变细胞内 TFV 和 TAF 的可用性，并损害 HIV 靶细胞的先天免疫反应。这项研究的独特之处在于它整合了我们对人类 FRT 中内分泌和免疫系统的理解，因为它与最有可能的细胞中的细胞内 TFV-DP 浓度直接相关。我们的目标是基于我们过去的研究，确定下一代化学避孕药（LNG 或 NET）如何影响 FRT HIV 靶细胞中杀菌剂（TFV 和 TAF）的可用性，以及炎症因子如何损害这些影响。 ，我们预计这些研究将证明某些化学避孕药/杀菌剂组合会损害杀菌剂的功效和对艾滋病毒感染的保护，特别是在存在炎症介质的情况下。这些研究将为下一步的开发提供重要的信息基础。生产组合化学避孕药和杀菌剂，以提供避孕和改善艾滋病毒感染的保护。