Defining the rectal mucosa in MSM at risk of HIV infection

描述(由申请者提供)：本建议概述了PI的全面职业发展计划，包括高级课程和基于实验室的免疫学实践培训，多学科指导，以及通过完成建议的研究项目而获得的实践经验。有了K23职业发展奖，凯利博士将发展必要的技能，以实现她的目标，即独立资助艾滋病毒转化研究职业，重点是生物医学艾滋病毒预防干预和艾滋病毒传播。凯利博士的最终目标是有朝一日为艾滋病毒预防科学做出重要贡献，包括为感染高危人群优化生物医学预防干预措施和疫苗开发。为了实现她的培训目标，凯利博士将在K23颁奖期间由免疫学家和艾滋病毒疫苗专家拉玛·阿马拉博士和具有男男性接触者艾滋病毒预防专业知识的流行病学家帕特里克·沙利文博士共同指导。她将在这一获奖期中脱颖而出，精通粘膜免疫学，再加上她之前在临床艾滋病毒药物、流行病学和临床/翻译研究方面的丰富经验，凯利博士将很好地定位于追求独立资助的研究生涯，并有一天成为生物医学艾滋病毒预防干预领域的领导者。在美国，男男性行为者(MSM)感染艾滋病毒的风险仍然最高，占2010年新增感染人数的63%，这突显了在这一人群中进行有效预防干预的迫切需要。包括暴露前预防(PrEP)、疫苗和杀微生物剂在内的生物医学预防战略的最新进展，使该领域围绕进一步为高危关键人群制定和实施这些干预措施而充满活力。然而，这些干预措施对MSM有效的一个潜在障碍是艾滋病毒通过直肠粘膜传播的相对容易，与阴道或阴茎传播相比，大约70%的感染发生在MSM中。此外，关于无保护的接受性肛交(URAI)如何改变直肠粘膜和粘膜HIV靶细胞群，人们知之甚少。我们假设，与不进行肛交的男性相比，性行为活跃的HIV阴性MSM与不进行肛交的男性相比，具有以下证据：(1)黏膜完整性降低，(2)黏膜炎症增加，(3)直肠黏膜可获得更多HIV靶细胞。为了验证这些假设，从事URAI和对照组的MSM将被招募到一项外周血液和直肠粘膜活检样本的纵向研究中。首先，在一项横断面研究中，我们将探索MSM和对照组直肠黏膜中整体基因表达的差异，特别是上皮细胞连接复合体、促炎细胞因子和细胞增殖/凋亡途径的基因表达。接下来，在基因表达分析的基础上，我们将选择差异表达的生物标志物，并用定量免疫组织化学方法检测MSM和对照组直肠黏膜上皮细胞层的纵向差异。最后，MSM和对照组的直肠粘膜中的CD4+和CD8+T细胞群在HIV共受体、CCR5的表达、记忆表型和激活状态方面的差异将被检测。进一步了解尿路感染如何影响直肠粘膜将在两个方面提供关键信息。首先，它可能有助于阐明当前和未来针对MSM高危人群的生物医学预防干预措施的不同效果。其次，它可能会建议其他辅助疗法来提高生物医学预防干预的效果。例如，如果进行URAI的MSM表现出更严重的炎症和/或直肠粘膜完整性降低，针对这些异常的辅助治疗与其他生物医学预防干预措施一起使用可以提高他们的疗效。 相关性：男男性行为者(MSM)继续不成比例地感染艾滋病毒。这项研究将考察从事无保护接受性肛交的HIV阴性MSM和不进行肛交的男性在粘膜完整性、炎症和直肠黏膜细胞数量方面的差异。在这些粘膜参数中看到的差异可能确定新的干预目标，并可能导致当前和未来生物医学艾滋病毒预防干预措施的有效性提高。

DESCRIPTION (provided by applicant): This proposal outlines a comprehensive career development plan for the PI consisting of advanced coursework and hands-on laboratory based training in immunology, multidisciplinary mentoring, and practical experience via the completion of the proposed research project. With the K23 Career Development Award, Dr. Kelley will develop the skills necessary to attain her goal of an independently funded HIV translational research career with a focus on biomedical HIV prevention interventions and HIV transmission. Dr. Kelley's ultimate goal is to one day make important contributions to the science of HIV prevention, including optimizing biomedical prevention interventions and vaccine development, for populations at high risk of infection. In order to attain her training goals, Dr. Kelley will b co-mentored during the K23 award period by an immunologist and HIV vaccinologist, Dr. Rama Amara, and an epidemiologist with expertise in HIV prevention for MSM, Dr. Patrick Sullivan. She will emerge from this award period skilled in mucosal immunology, which in combination with her previous extensive experience in clinical HIV medicine, epidemiology, and clinical/translational research, will position Dr. Kelley well to pursue an independently funded research career and one day be a leader in the field of biomedical HIV prevention interventions. Men who have sex with men (MSM) continue to have the highest risk for HIV infection in the US, accounting for 63% of new infections in 2010, underscoring the urgent need for effective prevention interventions in this population. Recent advances in biomedical prevention strategies including pre-exposure prophylaxis (PrEP), vaccines, and microbicides, have energized the field around further development and implementation of these interventions for key populations at higher risk. However, one potential barrier to the effectiveness of these interventions in MSM is the relative ease of HIV transmission across the rectal mucosa, where approximately 70% of infections occur among MSM, as compared to vaginal or penile transmission. In addition, very little is known about how unprotected receptive anal intercourse (URAI) may modify the rectal mucosa and mucosal HIV target cell populations. We hypothesize that sexually active HIV-negative MSM at risk for HIV infection who engage in URAI will have evidence of (1) reduced mucosal integrity, (2) more mucosal inflammation, and (3) greater HIV target cell availability in the rectal mucosa as compared to men who do not engage in anal intercourse. To test these hypotheses, MSM who engage in URAI and controls will be recruited into a longitudinal study with peripheral blood and rectal mucosal biopsy sampling. First, in a cross-sectional study, we will explore global gene expression differences between MSM and controls in the rectal mucosa with particular attention to gene expression of the epithelial cell junction complex, pro-inflammatory cytokines, and cell proliferation/apoptosis pathways. Next, based on the gene expression analyses, we will choose differentially expressed biomarkers and examine longitudinal differences between MSM and controls in the rectal mucosa epithelial cell layer with quantitative immunohistochemistry. Finally, differences in the CD4+ and CD8+ T cell populations in the rectal mucosa with respect to expression of the HIV co-receptor, CCR5, memory phenotypes, and activation status will be examined for MSM and controls. Advancing knowledge of how URAI affects the rectal mucosa will provide critical information in two areas. First, it may help to elucidate the differential efficacy of current and future biomedical preventin interventions specifically for MSM populations at high risk. Second, it may suggest other adjunctive therapies to improve efficacy of biomedical prevention interventions. For example, if MSM who engage in URAI exhibit greater inflammation and/or reduced rectal mucosal integrity, an adjunctive therapy that targets these abnormalities used in conjunction with other biomedical prevention interventions could improve their efficacy. RELEVANCE: Men who have sex with men (MSM) continue to be disproportionately affected by HIV. This study will examine differences in mucosal integrity, inflammation, and cell populations in the rectal mucosa between HIV negative MSM who engage in unprotected receptive anal intercourse and men who do not engage in anal intercourse. Differences seen in these mucosal parameters may identify new targets for intervention and could lead to improvements in efficacy of current and future biomedical HIV prevention interventions.