Reproductive Hormones and their impact on HIV-1 acquisition

生殖激素及其对 HIV-1 获得的影响

• 批准号: 8457131
• 负责人: SUSAN CU-UVIN
• 金额: $ 45.15万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-14 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457131
• 关键词: Acetates; Affect; Animals; Atrophic; Biology; Biopsy; CD4 Positive T Lymphocytes; Cells; Cervical; Cervix Uteri; Chemical Agents; Clinical Research; Cream; Data; Dependency; Dose; Dyspareunia; Enrollment; Environment; Epithelial; Epithelium; Estrogens; Excision; Exposure to; Female; Fertility; Genital system; HIV-1; Hormonal; Hormones; Human; Hysterectomy; Individual; Infection; Injury; Integration Host Factors; Life; Life Cycle Stages; Low Dose Oral Contraceptives; Luteal Phase; Macaca; Mediating; Menopause; Menstrual cycle; Nonoxynol 9; Oral Contraceptives; Organ Culture Techniques; Pattern; Phase; Postmenopause; Predisposition; Premenopause; Process; Progesterone; Proteins; Proteomics; Reproductive Health; Research Design; Risk; SIV; Safety; Simplexvirus; Site; Specimen; Staging; Symptoms; System; Tight Junctions; Tissues; Vagina; Vaginal Itching; Viral; Virus; Woman; base; cervicovaginal; cohort; genome wide association study; hormonal contraception; in vivo; irritation; macrophage; pressure; reproductive; reproductive hormone; response; simian human immunodeficiency virus; transmission process

DESCRIPTION (provided by applicant): The female genital tract is a gateway to HIV-1 infection and presents multiple potential anatomically distinct sites for HIV-1 transmission. In pre-menopausal women, fluctuating levels of endogenous reproductive hormones during the menstrual cycle induce morphological, immunological and proteomic changes in all compartments of the genital tract. More than 300 million women regulate fertility by hormonal contraception. Upon reaching menopause, some women begin exogenous hormone treatment to alleviate symptoms of vaginal atrophy. The impact of endogenous/exogenous reproductive hormones on HIV-1 acquisition in women is unknown. The unifying hypothesis of this proposal is that reproductive hormones alter HIV-1 acquisition risk by impacting host factors that regulate HIV-1 entry into the cervicovaginal tract and replication in mucosal CD4+ T lymphocytes and macrophages. We propose the following specific aims. (Aim 1) To quantify the effect of exogenous and endogenous reproductive hormones on HIV-1 susceptibility of the reproductive tract, (Aim 2) To determine whether reproductive hormones alter the mechanisms responsible for HIV-1 transmission through cervicovaginal epithelia, (Aim 3) To quantify the effect of reproductive hormones on HIV-1 dependency factors in the female genital tract. We will assemble a longitudinal cohort of healthy pre- and post-menopausal HIV-1 uninfected women. Subjects will undergo serial cervical and vaginal biopsy during different phases of the menstrual cycle, before/after starting hormonal contraception (high dose oral contraceptives vs. low dose oral contraceptives vs. DMPA) and before/after starting estrogenic creams. Tissues will be placed in organ culture and susceptibility to HIV-1 infection will be quantified and correlated to n vivo conditions of hormonal pressure. Given that the overriding emphasis of this RFA is on whether reproductive health serves as a co-morbid condition for HIV- 1, it is critical to determine whether the hormonal environment that acts as a master regulator of the female reproductive tract truly impacts HIV-1 acquisition.

描述（由申请人提供）：雌性生殖道是通往HIV-1感染的门户，并为HIV-1传播提供了多个潜在的解剖学上不同的位点。在绝经前妇女中，月经周期中内源性生殖激素水平波动诱导生殖道所有隔室的形态，免疫和蛋白质组变化。超过3亿妇女通过荷尔蒙避孕来调节生育能力。更年期后，一些妇女开始开始外源激素治疗，以减轻阴道萎缩的症状。内源/外源性生殖激素对女性HIV-1采集的影响尚不清楚。该提案的统一假设是，生殖激素通过影响调节HIV-1进入宫颈阴道界的宿主因素，改变HIV-1的获取风险，并在粘膜CD4+ T淋巴细胞和巨噬细胞中复制。我们提出以下特定目标。 （目的1）量化外源和内源性生殖激素对生殖道的HIV-1易感性的影响（目标2），以确定生殖激素是否改变了导致HIV-1通过宫颈阴道血管上的传播机制，以量化HIV-1的传播（AIM 3），以量化HORMONTARCTINE对HORPARDINACT keniv-1依赖性的影响。我们将组装成健康前和绝经后HIV-1未感染的妇女的纵向队列。受试者将在开始激素避孕药之前/之后（高剂量口服避孕药与低剂量的口服避孕药与DMPA与DMPA）和开始雌激素之前/之前/之后，在月经周期的不同阶段进行连续的宫颈和阴道活检。组织将被放置在器官培养物中，并将对HIV-1感染的敏感性进行量化并与荷尔蒙压力的n个体内条件相关。鉴于该RFA的重点是生殖健康是否是HIV-1的合并状况，因此确定至关重要 作为女性生殖道的主要调节剂的荷尔蒙环境是否都会影响HIV-1的获取。