Combination treatment for protection against HIV1 and pregnancy

预防 HIV1 和怀孕的联合治疗

• 批准号: 9245759
• 负责人: Janet Patricia Hapgood
• 金额: $ 21.22万
• 依托单位: UNIVERSITY OF CAPE TOWN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-18 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9245759
• 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; HIV-1 vaccine; Health; High Risk Woman; 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; 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; Vaginal delivery procedure; Virus Shedding; Woman; base; cervicovaginal; design; high risk; hormonal contraception; human female; immune function; insight; knowledge base; microbicide; pregnancy prevention; prophylactic; reproductive tract; 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.

 说明（由申请人提供）： 注射避孕药在艾滋病发病率和患病率很高的撒哈拉以南非洲地区得到广泛使用。避孕药具有多种不同形式，其给药方法和合成化合物（孕激素）的类型各不相同。 ）。临床研究表明，孕激素的作用是模仿孕激素，尤其是注射避孕药 Depo Provera，但其他药物则不然。孕激素会增加 HIV-1 感染和传播的风险，尤其是年轻女性，年轻女性面临的风险最大，而且最需要有效的避孕措施，这是一个巨大的公共卫生问题，影响着数百万人。由于目前观察性临床研究的数据没有提供有关激素避孕药，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，因此，世界各地的妇女，特别是发展中国家的妇女。迫切需要通过对人类女性生殖道组织的离体研究来阐明这一重要问题，这可能是获得孕激素对 HIV-1 相关基因表达和细胞功能的差异和直接影响及机制的最佳方法。控制孕激素反应的类固醇受体在孕激素的选择中发挥着关键作用，尽管不同的孕激素通过孕激素受体表现出相似的作用机制，但它们对调节免疫功能和基因的表达具有非常不同的脱靶效应。许多细胞通过与其他类固醇受体（例如皮质醇和雄激素受体）结合，本研究将重点研究四种不同的孕激素在生理相关浓度下对先前被认为对 HIV 具有重要作用的选定基因表达的影响和作用机制。 -1 在女性生殖道中的传播和发病机制将在几种 HIV-1 靶细胞和组织模型中进行体外研究，包括宫颈组织外植体、原代生殖器上皮细胞、外周血单核细胞和分离的 T 细胞和阴道给予抗逆转录病毒（ARV）药物作为杀微生物剂已成为一种潜在有效的预防策略，阴道给予联合抗逆转录病毒药物与孕激素避孕药为预防 HIV-1 感染和预防妊娠提供了一种有吸引力的策略。然而，关于孕激素避孕药与抗逆转录病毒药物联合使用的最佳选择的信息有限，需要进行详细的离体模型研究来确定孕激素和抗逆转录病毒药物的最佳且安全的组合。将进行针对炎症、生殖道屏障完整性、关键防御分子分泌的影响的机制研究，以及针对类固醇受体水平如何影响这些过程的研究，结果将为单独选择孕激素和联合孕激素提供重要见解。与 ARV 联合使用可最大程度地保护年轻女性免受 HIV-1 感染。