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实验室的免疫学实践培训，多学科指导以及通过完成拟议研究项目的实践经验。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职业生涯的目标，重点是生物医学艾滋病毒预防干预措施和艾滋病毒传播。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疫苗开发，以应对高感染风险人群。为了实现她的培训目标，Kelley博士将在K23奖期间B免疫学家和HIV疫苗学家拉马阿马拉博士和具有MSM艾滋病毒预防专业知识的流行病学家帕特里克Sullivan博士共同指导。她将从这个奖项期间出现熟练的粘膜免疫学，结合她以前在临床艾滋病毒医学，流行病学和临床/转化研究的丰富经验，将定位博士凯利很好地追求一个独立资助的研究生涯，并有一天是在生物医学艾滋病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年新增感染的63%，这突出表明迫切需要在这一人群中采取有效的预防干预措施。生物医学预防策略的最新进展，包括暴露前预防（PrEP），疫苗和杀微生物剂，为进一步开发和实施这些针对高危人群的干预措施提供了动力。然而，这些干预措施在MSM中有效性的一个潜在障碍是HIV通过直肠粘膜传播相对容易，与阴道或阴茎传播相比，大约70%的感染发生在MSM中。此外，很少有人知道如何无保护的接受性肛交（URAI）可能会修改直肠粘膜和粘膜HIV靶细胞群。我们假设，与不进行肛交的男性相比，进行URAI的性活跃的HIV阴性MSM有HIV感染风险，将有证据表明（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，MSM谁从事URAI和对照组将被招募到一个纵向研究与外周血和直肠粘膜活检标本。首先，在横断面研究中，我们将探讨全球MSM和控制直肠粘膜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的差异，特别注意。接下来，基于基因表达分析，我们将选择差异表达的生物标志物，并通过定量免疫组织化学方法研究MSM和对照组直肠粘膜上皮细胞层的纵向差异。最后，将检查MSM和对照组直肠粘膜中CD 4+和CD 8 + T细胞群在HIV辅助受体CCR 5表达、记忆表型和激活状态方面的差异。进一步了解URAI如何影响直肠粘膜将在两个方面提供重要信息。首先，它可能有助于阐明目前和未来的生物医学预防干预措施，特别是在高风险的MSM人群的差异疗效。第二，它可能会建议其他预防性治疗，以提高生物医学预防干预措施的有效性。例如，如果从事URAI的MSM表现出更大的炎症和/或直肠粘膜完整性降低，则针对这些异常的预防性治疗与其他生物医学预防干预措施结合使用可以提高其疗效。 相关性：男男性行为者（MSM）继续不成比例地受到艾滋病毒的影响。本研究将探讨粘膜完整性，炎症，和细胞群之间的差异，在直肠粘膜HIV阴性的男男性接触者谁从事无保护的接受肛交和男性谁不从事肛交。这些粘膜参数的差异可能会发现新的干预目标，并可能导致改善目前和未来的生物医学艾滋病预防干预措施的疗效。

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.