Combination treatment for protection against HIV1 and pregnancy

 描述（由申请人提供）：注射避孕药在艾滋病发病率和流行率较高的撒哈拉以南非洲地区广泛使用。有许多不同形式的避孕方法，其在交付方法和合成化合物（孕激素）的类型上各不相同。孕激素的设计是为了模仿黄体酮的作用，黄体酮是有效的避孕成分。临床研究表明，一些避孕药，特别是注射避孕药Depo Provera，会增加艾滋病毒感染和传播的风险，特别是在年轻妇女中。年轻妇女面临的风险最大，也最需要有效避孕。获得负担得起和安全的避孕药具是一个巨大的公共卫生问题，影响到全世界，特别是发展中国家的数百万妇女。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安全性的足够信息，特别是注射用醋酸甲羟孕酮（MPA）或Depo Provera，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离体研究可能代表了获得关于孕激素对与HIV-1获得相关的基因表达和细胞功能的差异和直接影响及机制的答案的最佳方法。控制对孕激素反应的类固醇受体在选择孕激素中起关键作用。虽然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许多细胞过程的基因表达具有非常不同的脱靶效应，通过与其他类固醇受体结合，例如皮质醇和雄激素的受体。这项研究将集中在四种不同的孕激素的作用和机制，在生理相关的浓度，选择基因的表达，以前确定为重要的HIV-1的传播和发病机制，在女性生殖道。将在几种HIV-1靶细胞和组织模型（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细胞和树突状细胞）中研究体外效应。阴道给药抗逆转录病毒（ARV）药物作为杀微生物剂已成为一种潜在的有效预防策略。阴道分娩联合抗逆转录病毒药物与抗孕激素避孕药提供了一个有吸引力的策略，既预防艾滋病毒-1的收购和预防怀孕。然而，关于将抗逆转录病毒药物与联合收割机结合使用的最佳选择，现有信息有限。需要详细的离体模型研究来确定最佳和安全的组合的receistin和抗逆转录病毒。将进行机制研究，探讨对炎症、生殖道屏障完整性、关键防御分子分泌的影响，并研究类固醇受体水平如何影响这些过程。这些结果应该为选择单独使用和与抗逆转录病毒药物联合使用来最大限度地保护年轻女性免受HIV-1感染提供关键的见解。

 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.