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

了解高危 MSM 中的直肠 HIV 传播：年龄、性交和粘膜损伤

• 批准号: 9245391
• 负责人: Colleen F Kelley
• 金额: $ 63.04万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-24 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9245391
• 关键词: AIDS prevention; Abstinence; Adolescent; Adult; Age; Anal Sex; Anus; Area; Attenuated; Biological Assay; Biopsy; Biopsy Specimen; Cell Proliferation; Cells; Clinical Research; Coitus; Columnar Epithelium; Data; Development; Effectiveness; Enrollment; Environment; Exhibits; Exposure to; Family; Female; Flow Cytometry; HIV; HIV Infections; HIV vaccine; Image Analysis; Immune; Immune response; Immunohistochemistry; Immunologics; Immunology; Incidence; Infection; Infiltration; Inflammatory; Inflammatory Response; Injury; Measures; Mechanics; Mucositis; Mucous Membrane; Natural History; Outcome; Physiological; Population; Predisposition; Preventive Intervention; Recording of previous events; Rectum; Research; Research Infrastructure; Resolution; Risk; Seminal fluid; Sex Behavior; Site; Time; Time Study; Trauma; Vagina; Variant; Woman; adolescent men who have sex with men; age effect; age related; aged; cohort; condoms; cytokine; design; digital imaging; experimental study; follow-up; healing; high risk; improved; men; men who have sex with men; men' s group; microbiota; next generation sequencing; nonhuman primate; penis; programs; rectal; reproductive tract; response; transcriptome; transcriptome sequencing; transmission process; vaginal transmission

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.

项目概要 尽管男男性行为者 (MSM) 只占美国人口的 2%，但却占到了 67%。 2014年新增艾滋病感染者数，部分地区青少年男男性接触者发病率高得惊人。 MSM 中艾滋病毒生物医学预防干预措施有效性的一个潜在障碍是 HIV 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 与阴道或阴茎传播相比，该病被认为发生在 MSM 中。然而，大多数艾滋病毒 粘膜传播研究集中于女性和非人类灵长类动物的阴道传播， 然后进行推断并应用于了解 MSM 之间的直肠传播机制。 直肠粘膜具有单层柱状上皮，理论上更容易受到机械作用 性交过程中对阴道或阴茎的创伤大于阴道或阴茎，并且在性交过程中接触精液会导致亲 女性生殖道的炎症级联反应可能对直肠产生类似的影响。在我们的初步 通过对 41 名 18-45 岁成年 HIV 阴性 MSM 的数据分析，我们发现了独特的先天性和适应性促炎性 直肠粘膜对无套接受性肛交（CRAI）的免疫反应，以及多样性 参与 CRAI 的成年 MSM 与男性的直肠粘膜微生物群组成和组成存在差异 不与 MSM 进行肛交 (AI) 的人 参与 CRAI 使家庭更加丰富 普雷沃特拉科。在此应用中，我们建议扩展我们之前的研究，以研究诸如 年龄和间歇性、频繁的、双方同意的性活动可以影响直肠传播，并确定 与 CRAI 相关的粘膜炎症是否会导致损伤后粘膜愈合延迟。瞄准 1，我们将比较青少年 MSM 与最近首次肛交的直肠粘膜免疫环境， 从事 CRAI 5 年以上的成年 MSM，以及未从事最先进 AI 的男性 流式细胞术、RNA-Seq 和微生物群测序分析并检查对 HIV 的离体影响 直肠外植体激发实验的敏感性。在目标 2 中，我们将梳理直肠粘膜的影响 成年 MSM 群体中因有或没有精液暴露的偶发性肛交造成的创伤 在CRAI。最后，在目标 3 中，我们将检查参与 CRAI 的成年 MSM 是否表现出延迟直肠 高分辨率肛门镜检查期间直肠活检实验诱导损伤后的粘膜愈合 后续数字成像。我们将在我们成功的转化粘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，旨在了解以下因素： 可能影响 MSM 之间的直肠传播。更好地了解 MSM 中的直肠 HIV 传播 将为艾滋病毒生物医学预防干预措施的发展提供宝贵的信息，包括 艾滋病毒疫苗。