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

成熟、传染性和创伤（麻省理工学院）导致青少年对艾滋病毒的易感性

• 批准号: 9245320
• 负责人: Grace M Aldrovandi
• 金额: $ 63.22万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-24 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9245320
• 关键词: AIDS prevention; Address; Adolescence; Adolescent; Adolescent HIV risk; Adolescent Medicine; Adult; Anus; Applications Grants; Behavioral; Biological; Biological Factors; Biological Markers; Biopsy; Blood; Characteristics; Color; Data; Development; Endocrinologist; Environment; Epithelial; Estrogens; Future; Gastroenterologist; Gender; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; HIV; HIV Infections; HIV-1; HIV-infected adolescents; Hormonal; Hormones; Immune; Immune system; Immunologist; Immunology; Individual; Infection; Inflammation; Injury; Knowledge; Mass Spectrum Analysis; Measures; Microbe; Modeling; Mucous Membrane; Pathogenesis; Patient Self-Report; Phase; Physiological; Population; Predisposition; Prevention strategy; Process; Proteins; Proteomics; Puberty; Public Health; Ribosomal RNA; Risk; Risk Factors; Secondary to; Sex Behavior; Sexual Maturation; Shotguns; Specialist; Structure; Symbiosis; Technology; Testing; Testosterone; Tissue Model; Tissues; Trauma; Vagina; Vulnerable Populations; Woman; Youth; cohort; fluidity; gender nonconforming; health data; high risk population; hormone therapy; immune activation; indexing; insight; men; microbial; microbial community; microbiome; microbiota; mucosal site; pediatrician; protein biomarkers; protein expression; proteomic signature; rapid growth; rectal; reproductive; reproductive development; response; sex; sexual trauma; transgender; transmission process; young man

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.

项目摘要 青少年占全球新艾滋病毒感染的42％，这些感染中几乎有90％是 在整个生殖器粘膜1,2上获得。除了行为风险因素之外，戏剧性的影响， 青少年生殖发育期间肛门和阴道粘膜上激素的动态变化可能 驱动粘膜易受感染的脆弱性。经历的跨性别青少年的极端激素变化 跨性激素治疗可能导致该组1,3--的惊人25％传播率 6。该提案直接解决了在性别符合性别中HIV易感性的青少年生物学风险因素 （顺式）和跨性别（跨性别）青少年，利用反式的唯一激素操纵 个体来定义睾丸激素和雌激素对粘膜完整性和炎症的影响 肛门和阴道粘膜。与顺式青少年的常规青春期进行比较提供了机会 为了完善我们的理解性甾体类固醇的粘膜作用。我们将定义肛门生殖器的规范指标 使用16S rRNA测序和阴道蛋白的质谱蛋白质组学的微生物群落。 这些规范值将在血液激素水平，制革厂的性成熟和 自我报告的性活动（ACASI）的粘膜创伤在整个个人的进展中 通过：（1）顺式青少年的常规性成熟，或（2）在青春期荷尔蒙封锁期间 促性腺激素释放激素（GNRH），随后用跨性别激素进行性成熟 （雌激素，睾丸激素）在反式青少年中。我们将从顺式和跨性别青年中获得直肠活检， 并使用离体直肠组织模型来评估性类固醇激素，性创伤和 艾滋病毒感染的微生物群落。此外，我们将确定阴道的蛋白质组学特征 炎症，粘膜屏障破坏以及肛门生态微生物群落的差异可能是 与HIV敏感性有关。这项研究最终将表征性类固醇激素和 共同肛门生殖器微生物群落和阴道粘膜蛋白的性创伤 增加青少年粘膜HIV传播的风险。这项研究提供了迫切需要的公众 健康数据以阐明有助于艾滋病毒获取和发病机理的生物学风险因素 青少年种群，特别是生殖成熟和损伤对肛门生殖粘膜的影响 环境。获得的信息将为未来的假设生成提供重要的平台 涉及调节HIV易感性和有效生物医学HIV预防策略的研究 这个高度脆弱的人口。