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

项目总结 青少年占全球新增艾滋病毒感染的42%，而这些感染中几乎90%是 通过肛门生殖器粘膜获得的1，2。除了行为风险因素，戏剧性的， 青春期生殖发育期间肛门和阴道粘膜激素的动态变化可能 促进粘膜对艾滋病毒感染的易感性。变性青少年经历的极端荷尔蒙变化 跨性别激素治疗可能导致这一群体中令人震惊的25%的传播率，3- 6.这项建议直接解决了青少年在性别认同方面艾滋病毒易感性的生物风险因素 (顺式和跨性别者)青少年，利用跨性别者中独特的荷尔蒙控制 确定睾丸激素和雌激素对人体内粘膜完整性和炎症的影响 肛门和阴道粘膜。顺式青春期青少年与传统青春期的比较提供了机会 为了加深我们对性激素对粘膜的影响的理解。我们将定义肛门生殖的规范性指标 微生物群落利用16S rRNA测序和质谱仪对阴道蛋白进行蛋白质组学分析。 这些标准值将在血液激素水平、坦纳性成熟和 自我报告的性行为造成的粘膜损伤(ACASI)也贯穿于个体的发展过程 通过：(1)顺式青春期青少年的常规性成熟，或(2)青春期激素阻断 促性腺激素释放激素(GnRH)和随后的性成熟与跨性激素 (雌激素、睾丸素)在变性青少年中的作用。我们将从顺式和变性人青年身上获取直肠活组织检查， 并使用体外直肠组织模型评估性类固醇激素、性创伤和 微生物群落对艾滋病毒感染的影响。此外，我们将鉴定阴道的蛋白质组特征。 炎症，粘膜屏障破坏，以及肛门微生物群落的差异可能是 与艾滋病毒易感性有关。这项研究最终将特征性类固醇激素和 性创伤对共生性肛门微生物群落和阴道粘膜蛋白的影响 增加青少年感染艾滋病毒的风险。这项研究为急需的公众提供了 健康数据，以阐明导致艾滋病毒感染和高危人群发病机制的生物风险因素 青少年群体，特别是生殖成熟和损伤对肛门生殖粘膜的影响 环境。所获得的信息将为未来的假设生成提供一个重要的平台 针对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的研究 这些高度脆弱的人群。

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.