Combination treatment for protection against HIV1 and pregnancy

预防 HIV1 和怀孕的联合治疗

• 批准号: 8839440
• 负责人: Janet Patricia Hapgood
• 金额: $ 33.16万
• 依托单位: UNIVERSITY OF CAPE TOWN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-23 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8839440
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Affinity; Africa South of the Sahara; Androgens; Anti-HIV Agents; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Area; Basic Science; Binding; Biological; Cell model; Cell physiology; Cells; Cervical; Clinical; Clinical Research; Contraceptive Agents; Contraceptive methods; Data; Dendritic Cells; Depo Provera; Development; Dose; Epithelial Cells; Epithelium; Exhibits; Female; Gene Expression; Gene Targeting; Generations; Genes; Genetic Transcription; Genital system; Glucocorticoid Receptor; Goals; HIV; HIV-1; High Risk Woman; Hormonal; Hydrocortisone; In Vitro; Incidence; Infection; Inflammation; Inflammatory Response; Injectable; International; Investigation; Lead; Levonorgestrel; Light; Link; Medroxyprogesterone 17-Acetate; Methods; Molecular; Mucous Membrane; Nestorone; Norethindrone; Oral; Pathogenesis; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Play; Pregnancy; Prevalence; Prevention; Prevention strategy; Prevention therapy; Process; Progesterone; Progesterone Receptors; Progestins; Property; Public Health; Publishing; Receptor Signaling; Relative (related person); Research; Risk; Role; Safety; Series; Serum; Signal Pathway; Signal Transduction; Steroid Receptors; Study models; T-Lymphocyte; Tenofovir; Testing; Tissue Model; Tissue-Specific Gene Expression; Tissues; Vaccines; Vaginal delivery procedure; Virus Shedding; Woman; base; cervicovaginal; design; high risk; human female; immune function; insight; knowledge base; microbicide; pregnancy prevention; prophylactic; public health relevance; reproductive; response; transcription factor; transmission process; young woman

 DESCRIPTION (provided by applicant): Injectable contraceptives are extensively used in Sub-Saharan Africa, where the incidence and prevalence of AIDS is high. There are many different forms of contraception, which vary in the method of delivery and type of synthetic compound (progestin). Progestins are designed to mimic the actions of progesterone, the active contraceptive ingredient. Clinical studies suggest that some, in particular the injectable contraceptive Depo Provera, but not other progestins, increase the risk of HIV-1 infection and transmission, particularly in young women. Young women are most at risk and also have the greatest need for effective contraception. Access to affordable and safe contraception is an enormous public health issue, affecting millions of women worldwide and particularly in the developing world. Since the current data from observational clinical studies do not provide sufficient information regarding the safety of hormonal contraceptives, particularly injectable medroxyprogesterone acetate (MPA) or Depo Provera, more research is urgently required to shed light on this important issue. Ex vivo studies on human female reproductive tract tissue likely represent the best method to obtain answers about the differential and direct effects and mechanisms of progestins on gene expression and cell functions relevant to HIV-1 acquisition. Steroid receptors, which control responses to progestins, play a key role in choice of progestin. Although different progestins exhibit similar mechanisms of action via the progesterone receptor, they have very different off-target effects on expression of genes that regulate immune function and many cellular processes, via binding to other steroid receptors, such as those for cortisol and androgens. This study will focus on the effects and mechanisms of action of four different progestins, at physiologically relevant concentrations, on expression of select genes previously identified as being important in HIV-1 transmission and pathogenesis in the female genital tract. Effects will be investigated in vitro, in several HIV-1 target cell and tissue model, including cervical tissue explants, primary genital epithelial cells, peripheral blood mononuclear cells and isolated T-cells and dendritic cells. Vaginal delivery of anti-retroviral (ARV) drugs as microbicides has emerged as a potentially effective prophylactic strategy. Vaginal delivery of a combined ARV with a progestin contraceptive offers an attractive strategy for both prevention of HIV-1 acquisition and prevention of pregnancy. However, limited information is available regarding the best choice of progestin contraceptive to combine with an ARV. Detailed ex vivo model studies are needed to define the optimal and safe combination of progestin and antiretroviral. Mechanistic studies addressing the effects on inflammation, integrity of the genita tract barrier, secretion of key defense molecules, and studies addressing how steroid receptor levels affect these processes will be performed. The results should provide key insights into choice of progestin alone and in combination with ARV for maximal protection of young women from HIV-1 infection.

 描述(申请人提供)：在艾滋病发病率和流行率很高的撒哈拉以南非洲地区，注射避孕药得到了广泛的使用。避孕有许多不同的形式，不同的分娩方法和合成化合物(孕酮)的类型也不同。黄体酮的设计是为了模仿黄体酮的作用，黄体酮是一种有效的避孕成分。临床研究表明，一些，特别是注射避孕药Depo Provera，而不是其他孕激素，会增加艾滋病毒-1感染和传播的风险，特别是在年轻女性中。年轻女性面临的风险最大，也最需要有效的避孕措施。获得负担得起的安全避孕药具是一个巨大的公共卫生问题，影响到全世界数百万妇女，特别是发展中国家的妇女。由于目前来自观察性临床研究的数据没有提供关于激素避孕药，特别是注射用醋酸甲羟孕酮(MPA)或Depo Provera的安全性的足够信息，迫切需要更多的研究来阐明这一重要问题。对人类女性生殖道组织的体外研究可能是获得关于孕激素对与HIV-1感染相关的基因表达和细胞功能的差异和直接影响及其机制的最好方法。控制孕激素反应的类固醇受体在孕激素的选择中起着关键作用。尽管不同的孕激素通过孕酮受体表现出相似的作用机制，但它们通过与其他类固醇受体(如皮质醇和雄激素)结合，对调节免疫功能和许多细胞过程的基因的表达具有非常不同的靶外效应。这项研究将集中在四种不同的孕激素在生理上相关的浓度下，对以前被认为在女性生殖道中的HIV-1传播和发病机制中具有重要作用的特定基因的表达的影响和作用机制。在体外，将在几个HIV-1靶细胞和组织模型中观察其作用，包括宫颈组织外植体、原代生殖器上皮细胞、外周血单个核细胞以及分离的T细胞和树突状细胞。作为杀菌剂的抗逆转录病毒(ARV)药物经阴道给药已成为一种潜在的有效预防策略。联合应用抗逆转录病毒和黄体酮避孕药的阴道分娩为预防HIV-1感染和预防怀孕提供了一种有吸引力的策略。然而，关于黄体酮避孕药与抗逆转录病毒药物联合使用的最佳选择，可获得的信息有限。需要详细的体外模型研究来确定孕激素和抗逆转录病毒的最佳和安全的组合。将进行机制研究，解决对炎症的影响，Genita道屏障的完整性，关键防御分子的分泌，以及研究类固醇受体水平如何影响这些过程。这一结果应该为选择单独使用孕激素以及与抗逆转录病毒药物联合使用最大限度地保护年轻女性免受HIV-1感染提供关键的见解。