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. !

项目总结 直到最近，变性人群体的具体艾滋病毒预防需求没有得到足够的重视，而且 具体地说，艾滋病毒传播的生物学到目前为止一直研究不足。跨性别者女性 男男性行为(TGWSM)感染艾滋病毒的风险增加，全球艾滋病毒流行率约为 20%，感染几率是普通人群的48倍。进行无套接受性肛交 (CRAI)在TGWSM中很常见，艾滋病毒通过直肠传播的生理效率 粘膜促进了艾滋病毒的传播。从历史上看，TGWSM被归类为与之发生性关系的男性 男性(MSM)参与艾滋病毒预防研究，尽管他们独一无二，但由于推定直肠感染艾滋病毒的风险相似 心理社会、生物和预防需求。从生物学的角度来看，许多TGWSM使用异性 激素治疗对直肠粘膜的影响不确定。内源激素和外源激素的作用 在人类和动物模型中，女性生殖道被描述为雌激素通常被视为 阻止艾滋病毒传播和黄体酮促进传播；然而，很少有研究报道对 直肠粘膜。此外，已知肠粘膜是类固醇生成的，而结肠上皮细胞 表达雌激素受体β，提示外源性激素治疗可能对直肠有影响 可能会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 翻译黏膜免疫学项目具有非常成功的临床研究和保留 基础设施，旨在了解可能影响艾滋病毒直肠传播的因素并提出 为了检测跨性别激素治疗对直肠粘膜常驻细胞群的影响， TGWSM中的转录组和微生物组。此外，我们会利用香港现有的基础设施 Emory/CDC艾滋病毒/艾滋病临床试验股，并将我们的研究扩展到国际网站曼谷，以便 在我们的调查结果中进行全球比较。在目标1中，我们将比较1)TGWSM中HIV靶细胞的可用性 雌激素治疗；2)雌激素+孕激素治疗；3)两性MSM。我们还将 在启动跨性激素治疗前后检测TGWSM中HIV靶细胞的可用性 纵向队列。在目标2中，我们将用rna-seq方法比较杂交后代中不同群体之间的转录组。 在纵向队列中的横断面队列和开始跨性别激素治疗前后的队列中 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 在直肠黏膜微生物区系中与跨性激素治疗相关，以告知设计 未来的HIV预防干预临床试验。这项建议的首要目标是实现更好的 了解跨性激素对直肠粘膜的影响，将有助于优化目前的 生物医学艾滋病毒预防干预措施和加强未来干预措施的设计，包括有效的 TGWSM的疫苗。 好了！