Understanding Rectal HIV transmission among At-risk MSM: Age, Intercourse, and Mucosal Injur

项目总结 尽管只占美国人口的2%，但男男性行为者(MSM)占到了67% 2014年新增艾滋病毒感染，一些地区青少年男男性接触者的发病率高得令人震惊。 在男男性行为者中进行生物医学艾滋病毒预防干预的一个潜在障碍是 艾滋病毒通过直肠粘膜传播的生理效率，大约70%的感染是通过直肠粘膜传播的 与经阴道或阴茎传播相比，被认为发生在MSM中。然而，大多数艾滋病毒 粘膜传播研究主要集中在女性和非人类灵长类动物的阴道传播上， 然后将其外推并应用于了解MSM之间的直肠传播机制。 直肠粘膜只有一层柱状上皮，理论上更容易发生机械性病变。 性交过程中的创伤比阴道或阴茎更严重，性交过程中暴露在精液中会导致 女性生殖道中的炎性级联反应可能在直肠中有类似的影响。在我们的预赛中 年龄18-45岁的41名成年HIV阴性MSM的数据显示，我们显示出明显的先天和适应性促炎作用 直肠黏膜对无套式接受性肛交的免疫反应及其多样性 从事CRAI的成年男男性接触者的直肠粘膜微生物区系组成与男性不同 那些不与男男性接触者进行肛交(AI)的人为家庭增加了CRAI 雷公藤科。在此应用程序中，我们建议扩展我们之前的研究，以检查诸如 年龄和间歇性、频繁、两厢情愿的性行为可以影响直肠传播，并确定 与CRAI相关的粘膜炎症是否导致损伤后粘膜愈合延迟。在AIM 1，我们将比较青春期男男性接触者和最近首次肛交的男男性接触者的直肠粘膜免疫环境， 从事CRAI工作5年的成年MSM，以及不从事人工智能的最先进的男性 流式细胞术、RNA-Seq和微生物区系测序分析，并检查体外对HIV的影响 直肠外植体激发敏感性实验。在目标2中，我们将梳理出直肠粘膜的影响 成年男男性接触者队列中有或无精液暴露的间歇性肛交所致的创伤 在克雷。最后，在目标3中，我们将检查成年男男性接触者是否表现出直肠延迟。 高分辨率直肠镜术中直肠活检对实验性损伤后粘膜愈合的影响 后续数字成像。我们将在我们成功的翻译黏膜免疫学计划的基础上 非常成功的临床研究和保留基础设施，旨在了解 可能影响男男性接触者的直肠传播。更好地了解男男性接触者中HIV的直肠传播 将有助于制定生物医学艾滋病毒预防干预措施，包括 艾滋病疫苗。

PROJECT SUMMARY Despite making up only 2% of the US population, men who have sex with men (MSM) accounted for 67% of new HIV infections in 2014, and incidence rates among adolescent MSM are alarmingly high in some areas. One potential barrier to the effectiveness of biomedical HIV prevention interventions among MSM is the physiologic efficiency of HIV transmission across the rectal mucosa, where approximately 70% of infections are thought to occur among MSM, as compared to vaginal or penile transmission. However, the majority of HIV mucosal transmission research has concentrated on vaginal transmission in women and non-human primates, which is then extrapolated and applied to understanding the mechanisms of rectal transmission among MSM. The rectal mucosa, with its single layer of columnar epithelium, is theoretically more prone to mechanical trauma during sexual intercourse than the vagina or penis, and exposure to semen during coitus causes a pro- inflammatory cascade in the female genital tract that may have similar effects in the rectum. In our preliminary data with 41 adult HIV-negative MSM aged 18-45, we show a distinct innate and adaptive pro-inflammatory immune response to condomless receptive anal intercourse (CRAI) in the rectal mucosa, and that the diversity and composition of the rectal mucosal microbiota differ between adult MSM who engage in CRAI versus men who do not engage in anal intercourse (AI) with MSM engaging in CRAI being enriched for the family Prevotellaceae. In this application, we propose to expand our previous studies to examine how factors such as age and episodic, frequent, consensual sexual activity can influence rectal transmission, and to determine whether the mucosal inflammation associated with CRAI leads to delayed mucosal healing after injury. In Aim 1, we will compare the rectal mucosal immune milieu between adolescent MSM with recent anal sex debut, adult MSM who have engaged in CRAI for > 5 years, and men who do not engage in AI with state of the art flow cytometry, RNA-Seq, and microbiota sequencing assays and examine the ex vivo impact on HIV susceptibility with rectal explant challenge experiments. In Aim 2, we will tease out the effects of rectal mucosal trauma due to episodic anal intercourse with and without semen exposure in a cohort of adult MSM engaging in CRAI. Finally, in aim 3, we will examine whether adult MSM who engage in CRAI exhibit delayed rectal mucosal healing after experimentally induced injury with rectal biopsy during high resolution anoscopy with follow-up digital imaging. 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 transmission among MSM. A better understanding of rectal HIV transmission among MSM will contribute valuable information to the development of biomedical HIV prevention interventions, including an HIV vaccine.