Decoding mutualistic microbiota-B cell interactions in the HIV-1-infected gut: impact on immunological non-responders

项目摘要 肠道微生物组、粘膜免疫细胞和HIV-1病毒粒子通过密切的相互作用影响彼此的功能。 和多方面的相互作用，决定感染者的疾病结果。在这个多PI提案中， 我们将检验HIV-1感染引起粘膜免疫系统严重破坏的中心假设， 在开始联合抗逆转录病毒治疗（cART）后，该系统未消退。通过 HIV-1阻断了微生物群和宿主免疫系统之间的关键信号， 导致生态失调的免疫改变后者触发了一个自我延续的、适应不良的反馈回路 它损害病毒准种的调节，促进HIV-1病毒粒子在肠道的持久存在， 在开始cART后，患者亚组的免疫重建不理想。的目的 这项研究计划将通过一个独特的合作努力，涉及三个高度 互补群体。Saurabh Mehandru博士，PI，是一名训练有素的胃肠病学家，拥有超过15年的经验， 在HIV-1感染领域的经验及其对粘膜免疫影响的几项关键贡献。他 将招募受感染的受试者，获得肠道组织，并沿着沿着描绘肠道和全身免疫群体。 HIV-1在肠道中的储存库（目标1）。Andrea Cerutti博士，联合PI，是世界知名的生物学专家， 来自健康和HIV-1感染个体的粘膜B细胞。他将研究肠道伊加反应， HIV-1感染的肠粘膜，重点是B细胞个体发育，克隆型结构和细菌反应性， IgA 1和IgA 2亚类。他还将定义不平衡的IgA 1和IgA 2反应对微生物的影响。 易位，肠道炎症和HIV-1复制（目的2）。Jeremiah Faith，Co-PI，是一位国际 他是微生物组研究领域公认的领导者，对该领域做出了几项开创性贡献。他将描述 HIV-1诱导的肠道微生物组改变及其对HIV-1诱导的粘膜伊加扰动的影响 他还将使用携带HIV-1感染患者或健康对照的肠道微生物群的gnotobiotic小鼠 测试cART对肠道细菌的影响，与宿主疾病状态无关（目的3）。

Project Summary The gut microbiome, mucosal immune cells and HIV-1 virions influence each other's functions through intimate and multifaceted interactions that determine disease outcomes in infected individuals. In this multi-PI proposal, we will test the central hypothesis that HIV-1 infection causes a profound disruption of the mucosal immune system, which does not resolve following the initiation of combination antiretroviral therapy (cART). By interrupting key signals between the microbiota and the host's immune system, HIV-1 elicits profound intestinal immune alterations that cause dysbiosis. This latter triggers a self-perpetuating, maladaptive feedback loop that impairs the regulation of viral quasispecies, promotes intestinal persistence of HIV-1 virions and, in a subset of patients, causes suboptimal immunological reconstitution following initiation of cART. The aims of this research program will be achieved through a unique collaborative effort involving three highly complementary groups. Dr. Saurabh Mehandru, PI, is a trained gastroenterologist with more than 15 years of experience in the field of HIV-1 infection and several key contributions on its impact in mucosal immunity. He will recruit infected subjects, obtain gut tissue, and profile intestinal and systemic immune populations along with HIV-1 reservoirs in the gut (Aim 1). Dr. Andrea Cerutti, Co-PI, is a world-renowned expert in the biology of mucosal B cells from both healthy and HIV-1-infected individuals. He will study intestinal IgA responses in the HIV-1-infected gut mucosa, focusing on the B cell ontogeny, clonotypic architecture and bacterial reactivity of IgA1 and IgA2 subclasses. He will also define the impact of unbalanced IgA1 and IgA2 responses on microbial translocation, gut inflammation and HIV-1 replication (Aim 2). Dr. Jeremiah Faith, Co-PI, is an internationally recognized leader in microbiome research, with several seminal contributions to this field. He will characterize HIV-1-induced alterations of the gut microbiome and their impact on HIV-1-induced mucosal IgA perturbations. He will also use gnotobiotic mice harboring the gut microbiota from HIV-1-infected patients or healthy controls to test the impact of cART on intestinal commensal bacteria independently of the host disease status (Aim 3).