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.

项目概要 全球新发艾滋病毒感染者中有 42% 是青少年，其中近 90% 是由青少年感染的 穿过肛门生殖器粘膜获得1,2。除了行为风险因素之外，戏剧性的影响， 青春期生殖发育过程中肛门和阴道粘膜激素的动态变化可能 导致粘膜易受艾滋病毒感染。跨性别青少年经历的极端荷尔蒙变化 跨性别激素治疗可能导致该群体中 25% 的惊人传播率1,3- 6. 该提案直接解决了性别一致的青少年艾滋病毒易感性的生物学危险因素。 （顺）和变性（跨）青少年，利用跨性别独特的荷尔蒙操纵 个体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。与顺式青少年的传统青春期进行比较提供了机会 加深我们对性类固醇对粘膜作用的理解。我们将定义肛门生殖器的规范指标 使用 16s rRNA 测序和阴道蛋白质质谱蛋白质组学研究微生物群落。 这些标准值将根据血液激素水平、坦纳性成熟度和 在个体的整个发展过程中，自我报告的性活动（ACASI）造成的粘膜损伤 通过：（1）顺式青少年的常规性成熟，或（2）在青春期激素阻断期间 促性腺激素释放激素 (GnRH)，以及随后的跨性别激素性成熟 （雌激素、睾酮）在跨性别青少年中。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，我们将鉴定阴道的蛋白质组学特征 炎症、粘膜屏障破坏以及肛门生殖器微生物群落的差异可能是 与艾滋病毒易感性有关。这项研究将最终描述性类固醇激素的影响和 性创伤对共生肛门生殖器微生物群落和阴道粘膜蛋白的影响 增加青少年粘膜艾滋病毒传播的风险。这项研究为公众提供了迫切需要的 健康数据，以澄清导致高危人群感染艾滋病毒和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器粘膜的影响 环境。获得的信息将为未来的假设生成提供重要平台 解决艾滋病毒易感性调节和有效的生物医学艾滋病毒预防策略的研究 这个高度脆弱的人群。