Chemical Contraceptive Control of Microbicides in the Female Reproductive Tract

 描述（由申请人提供）：迫切需要防止HIV-1通过性传播给妇女。在世界范围内，70%的新病例是通过性交传播的，女性比男性更容易感染。使用多用途预防技术方法，我们将测试以下总体假设：在不存在或存在炎症的情况下，一些化学避孕药直接作用于女性生殖道（FRT）CD 4 +T细胞和巨噬细胞，并通过上皮细胞和成纤维细胞间接作用于女性生殖道（FRT）CD 4 +T细胞和巨噬细胞，以降低TFV二磷酸（TFV-DP）的可用性，TFV和TFV阿拉芬胺（TAF）的生物活性形式，从而增加妇女感染艾滋病毒的风险。由于较新的孕激素化学避孕药（LNG：左炔诺孕酮和NET：炔诺酮）的副作用比醋酸甲羟孕酮（MPA）少，因此该建议的核心是比较MPA与LNG和NET，以及它们对TFV和TAF的影响，这可能是下一代杀微生物剂，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。本提案有3个目标，测试以下假设：目标1。化学避孕药直接作用于改变人FRT组织中HIV靶细胞中TFV-DP的细胞内水平，从而损害杀微生物剂对HIV感染的保护。目标2.化学避孕药通过改变TFV-DP形成和/或降解所必需的酶的机制来调节HIV靶细胞中的TFV-DP浓度。目标3。炎症因子（PRR配体）和化学避孕药改变TFV和TAF的细胞内利用度，并损害来自FRT的HIV靶细胞的先天免疫应答。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，因为它直接关系到最有可能被HIV感染的细胞中的细胞内TFV-DP浓度。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靶细胞中杀微生物剂（TFV和TAF）的可用性，以及炎症因子如何影响这些作用。基于我们过去的研究，我们希望这些研究将证明，一些化学避孕药/杀微生物剂组合，将损害杀微生物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。这些研究将为开发下一代化学避孕药和杀微生物剂复方制剂提供必要的信息基础，以提供避孕和更好的预防艾滋病毒感染的保护。

 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.