Defining the rectal mucosa in MSM at risk of HIV infection

描述（由申请人提供）：该提案概述了PI的全面职业发展计划，包括高级课程和基于免疫学的动手实验室培训，多学科指导，以及通过完成拟议的研究项目获得的实践经验。凭借K23职业发展奖，凯利博士将发展必要的技能，以实现她独立资助的艾滋病毒转化研究事业的目标，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一天为艾滋病毒预防科学做出重要贡献，包括优化生物医学预防干预措施和为感染高风险人群开发疫苗。为了实现她的培训目标，在K23奖励期间，Kelley博士将由免疫学家和艾滋病毒疫苗学家Rama Amara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Patrick Sullivan博士共同指导。她将在此奖项期间熟练掌握粘膜免疫学，结合她之前在临床HIV医学，流行病学和临床/转化研究方面的丰富经验，将使Kelley博士能够很好地追求独立资助的研究事业，并有一天成为生物医学HIV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年新感染病例的63%，这突显了对这一人群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，激励了该领域进一步制定和实施针对高危关键人群的这些干预措施。然而，这些干预措施对男男性行为者有效性的一个潜在障碍是艾滋病毒相对容易通过直肠粘膜传播，与阴道或阴茎传播相比，大约70%的感染发生在男男性行为者中。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靶细胞群的了解甚少。我们假设，与不进行肛交的男性相比，性活跃的HIV阴性男男性接触者有感染HIV的风险，他们有证据表明：(1)粘膜完整性降低，(2)粘膜炎症更多，(3)直肠粘膜中HIV靶细胞的可用性更高。为了验证这些假设，参与URAI的男男性行为者和对照组将被招募到一项纵向研究中，进行外周血和直肠粘膜活检取样。首先，在一项横断面研究中，我们将探讨MSM和对照组在直肠粘膜中的整体基因表达差异，特别关注上皮细胞连接复合物、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，并使用定量免疫组织化学方法检测MSM与对照组在直肠粘膜上皮细胞层中的纵向差异。最后，在MSM和对照组中，直肠粘膜CD4+和CD8+ T细胞群在HIV共受体、CCR5、记忆表型和激活状态的表达方面的差异将被检查。提高对直肠粘膜的认知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生物医学预防干预措施的不同功效，特别是对高危男同性恋人群。其次，它可能建议其他辅助治疗，以提高生物医学预防干预的疗效。例如，如果参与URAI的MSM表现出更大的炎症和/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相结合，可以提高其疗效。

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.