STI and Implications for HIV Transmission and Prevention

项目摘要 尽管只占美国人口的2%，但男男性行为者（MSM）占美国人口的67%。 2014年新的艾滋病毒感染，以及在一些地区青少年男男性行为者的发病率高得惊人。 在男男性行为者中，生物医学艾滋病毒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，其中约70%的感染 被认为发生在男男性接触者中。然而，大多数HIV粘膜传播研究 集中在女性和非人类灵长类动物的阴道传播，然后外推到 了解MSM之间直肠传播的机制。此外，炎症在 直肠粘膜归因于细菌性性传播感染（STI），包括衣原体（CT）、淋病 (GC)，和梅毒，迄今为止一直没有得到充分的研究，尽管性传播感染在男男性行为者中造成了巨大的负担， 影响艾滋病毒传播。我们以前已经表明，直肠STI，即使在常规的设置， 筛查和治疗与HIV阴性MSM队列中的HIV血清转化相关。艾滋病毒 阳性MSM，我们先前的工作表明，直肠脱落的艾滋病毒仍然很低，在男性的抑制 抗逆转录病毒治疗（ART）与直肠GC和/或CT;然而，粘膜取样不是最佳的， 在本研究中检测到低水平脱落。在没有直肠STI的情况下，本研究中提供的初步数据 应用于18 - 45岁的成人HIV阴性MSM显示出明显的先天性和适应性促炎性 直肠粘膜对无安全套接受性肛交（CRAI）的免疫反应， 直肠粘膜微生物群的组成在从事CRAI的成年MSM与男性之间存在差异 谁不从事肛交（AI）与男男性接触者从事CRAI正在丰富的家庭 普氏菌科在本申请中，我们建议扩大我们对MSM直肠粘膜的研究， 细菌STI对直肠粘膜驻留细胞群（aim1）和微生物组（aim2）的影响。在 目的3，我们将研究STI治疗后炎症的消退及其对体外HIV感染的影响， 直肠粘膜我们将建立在我们成功的翻译粘膜免疫学计划与高度 成功的临床研究和保留基础设施，旨在了解可能 影响MSM之间直肠传播。更好地了解直肠中对STI的宿主反应 将有助于设计生物医学艾滋病毒和细菌性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.