Maturation, Infectibility, and Trauma(MIT) Contributes to HIV Susceptibility in Adolescents

项目摘要 青少年占全球艾滋病毒新感染者的42%，其中近90%的感染者是 通过肛门生殖器粘膜获得1，2.除了行为风险因素，戏剧性的影响， 在青春期生殖发育期间，肛门和阴道粘膜上激素的动态变化可能 使粘膜易受HIV感染。变性青少年经历的极端荷尔蒙变化 交叉性激素治疗可能导致该组中惊人的25%的传播率1，3- 6.该提案直接针对性别一致性中艾滋病毒易感性的青少年生物风险因素 (cis)和跨性别（跨）青少年，利用独特的荷尔蒙操纵在跨 个体，以确定睾酮和雌激素对粘膜完整性和炎症的影响， 肛门和阴道粘膜与传统青春期的比较，在CIS青少年提供了机会， 来完善我们对性类固醇的粘膜作用的理解我们将定义肛门生殖器的规范性指标 使用16 s rRNA测序和阴道蛋白质质谱蛋白质组学分析微生物群落。 这些标准值将在血液激素水平、坦纳性成熟和 自我报告的性活动（ACASI）引起的粘膜创伤， 通过：（1）顺式青春期的常规性成熟，或（2）青春期激素阻滞期间， 促性腺激素释放激素（GnRH）和随后的性成熟与跨性别激素 （雌激素，睾酮）在跨性别青少年。我们将从顺性别和跨性别青年中获取直肠活检， 并使用离体直肠组织模型来评估性类固醇激素、性创伤和 微生物群落对艾滋病毒感染的影响。此外，我们将确定阴道分泌物的蛋白质组特征， 炎症、粘膜屏障破坏和肛门生殖器微生物群落的差异， 与艾滋病易感性有关。这项研究将最终描述性类固醇激素的作用， 性创伤对尿道肛门生殖器微生物群落和阴道粘膜蛋白的影响， 增加青少年粘膜HIV传播风险。这项研究提供了急需的公共 健康数据，以澄清生物风险因素，有助于艾滋病毒的收购和发病机制，在这些风险 青少年人群，特别是生殖成熟和损伤对肛门生殖器粘膜的影响 环境.所获得的信息将为未来的假设生成提供重要平台 研究解决艾滋病毒易感性的调节和有效的生物医学艾滋病毒预防策略， 这是一个非常脆弱的群体。

PROJECT SUMMARY Adolescents account for 42% of new HIV infections worldwide, and almost 90% of these infections are acquired across the anogenital mucosa1,2. Beyond behavioral risk factors, the influences of the dramatic, dynamic shifts in hormones during adolescent reproductive development on the anal and vaginal mucosa may drive mucosal vulnerability to HIV infection. Extreme hormonal shifts in transgender adolescents undergoing cross-sex hormone therapy may contribute to the alarmingly high 25% transmission rates seen in this group1,3- 6. This proposal directly addresses adolescent biologic risk factors for HIV susceptibility in gender conforming (cis) and transgender (trans) adolescents, taking advantage of the unique hormonal manipulation in trans individuals to define the influence of testosterone and estrogen on mucosal integrity and inflammation within the anal and vaginal mucosa. Comparisons to conventional puberty in cis adolescents provide the opportunity to refine our understanding the mucosal effects of sex-steroids. We will define normative indices of anogenital microbial communities using 16s rRNA sequencing and mass spectrometry proteomics of vaginal proteins. These normative values will be evaluated in the context of blood hormone levels, Tanner sexual maturity, and mucosal trauma from self-reported sexual activity (ACASI) throughout the individual's progression either through: (1) conventional sexual maturation in cis adolescents, or (2) during pubertal hormonal blockade with gonadotropin-releasing hormone (GnRH), and subsequent sexual maturation with cross-sex hormones (estrogen, testosterone) in trans adolescents. We will obtain rectal biopsies from cis and trans gender youth, and use an ex vivo rectal tissue model to evaluate the impact of sex steroid hormones, sexual trauma and microbial communities on HIV infection. Furthermore, we will identify proteomic signatures of vaginal inflammation, mucosal barrier disruption, and differences in anogenital microbial communities that may be related to HIV susceptibility. This study will ultimately characterize the effects of sex steroid hormones and sexual trauma on commensal anogenital microbial communities and vaginal mucosal proteins that confer increase risk to mucosal HIV transmission in adolescents. This study provides desperately-needed public health data to clarify biologic risk factors that contribute to HIV acquisition and pathogenesis in these at-risk adolescent populations, in particular the effects of reproductive maturation and injury upon anogenital mucosal environments. The information gained will provide a significant platform for future hypothesis-generating studies that address modulation of HIV susceptibility and efficacious biomedical HIV prevention strategies in this highly vulnerable population.