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: 10447095
• 负责人: Colleen F Kelley
• 金额: $ 68.06万
• 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/10447095
• 关键词: AIDS prevention; AIDS/HIV problem; Anal Sex; Animals; Attention; Bacteroidaceae; Biological; Biology of HIV Transmission; Biopsy; CD4 Positive T Lymphocytes; Cells; Centers for Disease Control and Prevention (U.S.); Clinical Research; Clinical Trials; Clinical Trials Unit; 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; Hormones; Immune; Immunohistochemistry; Immunologics; Immunology; Infection; Inflammatory; Infrastructure; International; Intervention; Intestinal Mucosa; Knowledge; Longitudinal cohort; Modeling; Mucositis; Mucous Membrane; Phenotype; Physiological; Pilot Projects; Population; Population Biology; Predisposition; Prevalence; Prevention; Prevention Research; Progesterone; Rectum; Reporting; Research; Risk; Sampling; Site; Thailand; Time; Vaccines; Work; base; 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. !

项目摘要 直到最近，跨性别人群的特定艾滋病毒预防需求还没有得到足够的关注，并且 迄今为止，艾滋病毒传播的生物学已被理解。具有变性女性 与男性的性行为（TGWSM）大约有艾滋病毒患病率的艾滋病毒收购风险较高 20％和感染几率是普通人群的48倍。进行无避孕套的接受肛门性交 （CRAI）在TGWSM中很常见，并且直肠跨度HIV的生理效率 粘膜最爱的HIV传播。从历史上看，TGWSM与与之发生性关系的男人分组 男性（MSM）在艾滋病毒预防研究中出现了类似的直肠艾滋病毒风险 社会心理，生物学和预防需求。从生物学的角度来看，许多TGWSM使用跨性别 激素疗法具有不确定的直肠粘膜作用。内源性和外源性恐怖的影响 在人类和动物模型中，女性生殖道已被描述为雌激素通常被视为 阻碍艾滋病毒传播和孕激素促进传播；但是，很少有研究报告对 直肠粘膜。另外，已知肠粘膜是类固醇生成的，结肠上皮细胞 表达雌激素受体β，表明外源性马酮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，我们将基于我们的成功 具有非常成功的临床研究和保留率的翻译粘膜免疫学计划 旨在理解可能影响直肠HIV传播和建议的因素的基础设施 为了检查跨性别霍尼治疗对直肠粘膜居民细胞种群的影响， TGWSM中的转录组和微生物组。此外，我们将利用 Emory/CDC HIV/AIDS临床试验单元，并将我们的研究扩展到曼谷的国际网站，以便 在我们的发现中进行全球比较。在AIM 1中，我们将比较1）TGWSM中的HIV目标细胞的可用性 雌激素疗法，2）TGWSM在雌激素 +孕酮治疗上，3）sisgender MSM。我们也会 在启动跨性别马酮治疗之前和之后，检查TGWSM中的HIV靶细胞可用性 纵向队列。在AIM 2中，我们将通过RNA-seq比较跨组中的RNA-seq 截面队列以及在纵向队列中启动跨性别霍尼治疗之前和之后 确定生物医学艾滋病毒预防干预措施的新目标。最后，在AIM 3中，我们将定义差异 在与跨性别疗法相关的直肠粘膜微生物群中 未来的HIV预防干预临床试验。该提案的总体目标是实现更好的 了解跨性激素的直肠粘膜作用，这将允许优化电流 生物医学艾滋病毒预防干预措施并增强未来干预措施的设计，包括有效 疫苗，用于TGWSM。 呢