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

项目摘要 直到最近，变性人群的具体艾滋病毒预防需求没有得到足够的重视， 具体来说，艾滋病毒传播的生物学至今尚未得到充分研究。有过这种经历的跨性别女性 与男性发生性行为（TGWSM）的人感染艾滋病毒的风险较高，全球艾滋病毒流行率约为 感染率是普通人群的48倍进行无安全套的肛交 （CRAI）在TGWSM中很常见，HIV通过直肠传播的生理效率 粘膜促进艾滋病毒传播。从历史上看，TGWSM被归类为与男性发生性关系的男性， 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，尽管他们独特的 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作用 在人类和动物模型的女性生殖道中，雌激素通常被视为 阻碍艾滋病毒传播和孕激素促进传播;然而，很少有研究报告的影响， 直肠粘膜此外，肠粘膜已知是类固醇生成的，并且结肠上皮细胞 表达雌激素受体β，表明外源性激素治疗可能对直肠癌有影响。 可能影响HIV传播的粘膜。在这个应用程序中，我们将建立在我们成功的 翻译粘膜免疫学计划，具有非常成功的临床研究和保留 该基础设施旨在了解可能影响直肠HIV传播的因素，并提出 为了检查交叉性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，我们会善用 埃默里/疾病预防控制中心艾滋病毒/艾滋病临床试验单位，并扩大我们的研究到一个国际网站，曼谷，以 在我们的研究结果中进行全球比较。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）雌激素+孕激素治疗的TGWSM，和3）顺性别MSM。我们还将 检查TGWSM在开始交叉性激素治疗前后的HIV靶细胞可用性， 纵向队列在目标2中，我们将通过RNA-seq比较交叉研究中各组之间的转录组。 在纵向队列中，在开始交叉性激素治疗之前和之后， 确定生物医学艾滋病毒预防干预措施的新目标。最后，在目标3中，我们将定义差异 在与交叉性激素治疗相关的直肠粘膜微生物群中， 未来的艾滋病预防干预临床试验。本提案的总体目标是实现更好的 了解跨性别激素对直肠粘膜的影响，从而优化当前的治疗方案 艾滋病毒生物医学预防干预措施，并加强未来干预措施的设计，包括有效的 疫苗，用于TGWSM。 !

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. !