STI and Implications for HIV Transmission and Prevention

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 被认为发生在男男性接触者中。然而，大多数关于艾滋病毒粘膜传播的研究已经 集中在女性和非人类灵长类动物的阴道传播上，然后推断为 了解男男性接触者的直肠传播机制。此外，炎症在血管紧张性疾病中的作用 直肠粘膜可归因于细菌性传播感染(STI)，包括衣原体(CT)、淋病 (GC)和梅毒，尽管MSM和他们的STI造成了巨大的负担，但迄今为止对梅毒的研究还不够充分 对艾滋病毒传播的影响。我们以前已经证明，直肠STI，即使在常规的设置下 筛查和治疗与HIV阴性男男性接触者队列中的HIV血清转换有关。针对HIV病毒 阳性的男男性接触者，我们先前的工作表明，在抑制的男性中，艾滋病毒的直肠排出保持在低水平 使用直肠GC和/或CT进行抗逆转录病毒治疗(ART)；然而，粘膜采样并不是治疗 在这项研究中检测到低水平的脱落。在没有直肠STI的情况下，本研究提供的初步数据 18-45岁成年HIV阴性MSM的应用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。在这项应用中，我们建议扩大我们对MSM的直肠粘膜研究，以检查 细菌STI对直肠粘膜驻留细胞群(AIM1)和微生物群(AIM2)的影响。在……里面 目的3、研究STI治疗后炎症的消退及其对体外HIV感染的影响。 直肠粘膜。我们将在我们成功的翻译黏膜免疫学计划的基础上，通过高度的 成功的临床研究和保留基础设施，旨在了解可能 对男男性接触者直肠传播的影响。更好地了解宿主对直肠STI的反应 将有助于设计生物医学艾滋病毒和细菌性传播感染预防机制，包括有效的 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. However, the majority of HIV mucosal transmission research has concentrated on vaginal transmission in women and non-human primates, which is then extrapolated to understanding the mechanisms of rectal transmission among MSM. In addition, the role of inflammation in the rectal mucosa attributed to bacterial sexually transmitted infections (STI), including Chlamydia (CT), Gonorrhea (GC), and syphilis, has been understudied to date despite the tremendous burden of STI in MSM and their influence on HIV transmission. We have previously shown that rectal STI, even in the setting of routine screening and treatment, is associated with HIV seroconversion in a cohort of HIV-negative MSM. For HIV positive MSM, our prior work shows that rectal shedding of HIV remains low in men on suppressive antiretroviral therapy (ART) with rectal GC and/or CT; however, sampling of the mucosa was not optimal to detect low level shedding in this study. In the absence of rectal STI, preliminary data presented in this application with adult HIV-negative MSM aged 18-45 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 rectal mucosal studies of MSM to examine the effect of bacterial STI on the rectal mucosal resident cellular populations (aim1) and the microbiome (aim2). In aim 3, we will study resolution of inflammation after treatment of STI and its effect on ex vivo HIV infection of the rectal mucosa. 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 the host response to STI in the rectum will be useful to the design of biomedical HIV and bacterial STI prevention mechanisms, including effective vaccines.