Understanding the rectal mucosal effects of cross-sex hormone therapy among US and Thai transgender women

了解跨性别激素治疗对美国和泰国变性女性直肠粘膜的影响

• 批准号: 10672350
• 负责人: Colleen F Kelley
• 金额: $ 66.91万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10672350
• 关键词: AIDS prevention; Anal Sex; Animals; Attention; Bacteroidaceae; Biological; Biology of HIV Transmission; Biopsy; CD4 Positive T Lymphocytes; Cells; Clinical Research; Clinical Trials; Clinical Trials Unit; Colon; Color; Cross-Sectional Studies; Development; Enrollment; Epithelial Cells; Estrogen Receptor beta; Estrogen Therapy; Estrogens; Exogenous Hormone Therapy; Exposure to; Female genitalia; Flow Cytometry; Future; Gene Expression Profile; General Population; Goals; Gonadal Steroid Hormones; HIV; HIV Infections; HIV Seronegativity; HIV prevention trial; HIV vaccine; HIV/AIDS; Hormones; Immune; Immunohistochemistry; Immunologics; Immunology; Infection; Inflammatory; Infrastructure; International; Intervention; Intestinal Mucosa; Knowledge; Longitudinal cohort; Modeling; Mucositis; Mucous Membrane; Phenotype; Physiological; Pilot Projects; Population; Predisposition; Prevalence; Prevention; Prevention Research; Progesterone; Rectum; Reporting; Research; Risk; Sampling; Site; Thailand; Vaccines; Work; cis-male; cohort; design; efficacy evaluation; experimental study; high risk men; hormone therapy; human model; immune activation; improved; inflammatory marker; men who have sex with men; microbiome; microbiota; mucosal microbiota; next generation sequencing; preventive intervention; programs; psychosocial; receptor expression; rectal; rectal HIV transmission; reproductive tract; transcriptome; transcriptome sequencing; transgender; transgender women; transgender women who have sex with men; transmission process; virtual

PROJECT SUMMARY Until recently, the specific HIV prevention needs of transgender populations received insufficient attention, and the biology of HIV transmission, specifically, has been understudied to date. Transgender women who have sex with men (TGWSM) are at elevated risk for HIV acquisition with global HIV prevalence rates approximately 20% and odds of infection 48 times the general population. Engaging in condomless receptive anal intercourse (CRAI) is common among TGWSM, and the physiologic efficiency of HIV transmission across the rectal mucosa facilitates HIV transmission. Historically, TGWSM have been grouped with men who have sex with men (MSM) in HIV prevention studies due to presumed similar risks of rectal HIV exposure despite their unique psychosocial, biologic, and prevention needs. From a biologic perspective, many TGWSM use cross-sex hormone therapy with uncertain rectal mucosal effects. The effects of endogenous and exogenous hormones in the human and animal-model female genital tract has been described with estrogen generally being seen as hindering HIV transmission and progesterone facilitating transmission; however, few studies report effects on the rectal mucosa. In addition, the intestinal mucosa is known to be steroidogenic, and colonic epithelial cells express estrogen receptor β, suggesting that exogenous hormone therapy likely has an effect on the rectal mucosa that could influence HIV transmission. In this application, we will build upon our successful translational mucosal immunology program with a highly successful clinical research and retention infrastructure that was designed to understand factors that may influence rectal HIV transmission and propose to examine the effects of cross-sex hormone therapy on the rectal mucosal resident cellular populations, transcriptome, and microbiome in TGWSM. In addition, we will capitalize on the existing infrastructure of the Emory/CDC HIV/AIDS Clinical Trials Unit and expand our studies to an international site, Bangkok, in order to make global comparisons in our findings. In aim 1, we will compare HIV target cell availability in 1) TGWSM on estrogen therapy, 2) TGWSM on estrogen + progesterone therapy, and 3) cisgender MSM. We will also examine HIV target cell availability in TGWSM before and after initiating cross-sex hormone therapy in a longitudinal cohort. In aim 2, we will compare the transcriptome by RNA-seq between groups in the cross- sectional cohort and before and after initiating cross-sex hormone therapy in the longitudinal cohort in order to identify new targets for biomedical HIV prevention interventions. Finally, in aim 3, we will define the differences in the rectal mucosal microbiota associated with cross-sex hormone therapy in order to inform the design of future HIV prevention intervention clinical trials. The overarching goal of this proposal is to achieve a better understanding of the rectal mucosal effects of cross-sex hormones that will allow for the optimization of current biomedical HIV prevention interventions and enhance design of future interventions, including an effective vaccine, for TGWSM. !

项目概要 直到最近，跨性别人群的具体艾滋病毒预防需求还没有受到足够的重视，并且 具体而言，迄今为止，人们对艾滋病毒传播的生物学尚未得到充分研究。跨性别女性有 男男性行为 (TGWSM) 感染艾滋病毒的风险较高，全球艾滋病毒患病率约为 20%，感染几率是一般人群的48倍。进行无套接受性肛交 (CRAI) 在 TGWSM 中很常见，HIV 经直肠传播的生理效率 粘膜有利于艾滋病毒的传播。从历史上看，TGWSM 被归为与以下对象发生性关系的男性： 男性（MSM）在艾滋病毒预防研究中由于假定直肠艾滋病毒暴露的风险相似，尽管其独特 社会心理、生物和预防需求。从生物学角度来看，许多 TGWSM 使用跨性别 激素治疗对直肠粘膜的影响不确定。内源性和外源性激素的影响 在人类和动物模型的女性生殖道中，雌激素通常被视为 阻碍艾滋病毒传播，孕激素促进传播；然而，很少有研究报告对 直肠粘膜。此外，已知肠粘膜具有类固醇生成作用，而结肠上皮细胞则具有类固醇生成作用。 表达雌激素受体β，表明外源性激素治疗可能对直肠有影响 可能影响艾滋病毒传播的粘膜。在此应用程序中，我们将在我们成功的基础上再接再厉 转化粘膜免疫学项目具有非常成功的临床研究和保留 旨在了解可能影响直肠艾滋病毒传播的因素并提出建议的基础设施 检查跨性别激素治疗对直肠粘膜驻留细胞群的影响， TGWSM 中的转录组和微生物组。此外，我们还将利用现有的基础设施 埃默里大学/疾病预防控制中心艾滋病毒/艾滋病临床试验单位并将我们的研究扩展到曼谷的国际地点，以便 对我们的研究结果进行全球比较。在目标 1 中，我们将比较 1) TGWSM 中的 HIV 靶细胞可用性 雌激素治疗，2) TGWSM 雌激素+黄体酮治疗，以及 3) 顺性别 MSM。我们还将 在开始跨性别激素治疗之前和之后检查 TGWSM 中 HIV 靶细胞的可用性 纵向队列。在目标 2 中，我们将通过 RNA-seq 比较跨组中的转录组 分段队列和纵向队列中开始跨性别激素治疗之前和之后，以便 确定生物医学艾滋病毒预防干预措施的新目标。最后，在目标 3 中，我们将定义差异 与跨性别激素治疗相关的直肠粘膜微生物群，以便为设计提供信息 未来的艾滋病毒预防干预临床试验。该提案的总体目标是实现更好的 了解跨性激素对直肠粘膜的影响，这将有助于优化当前的 生物医学艾滋病毒预防干预措施并加强未来干预措施的设计，包括有效的 疫苗，用于 TGWSM。 ！