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

项目摘要 肠道微生物群、粘膜免疫细胞和HIV-1病毒粒子通过相互作用影响彼此的功能 以及多方面的相互作用，决定了受感染个人的疾病结果。在这个多PI提案中， 我们将检验中心假设，即HIV-1感染会导致粘膜免疫功能的严重破坏。 系统，在开始联合抗逆转录病毒治疗(CART)后不能解决。通过 阻断微生物区系和宿主免疫系统之间的关键信号，HIV-1引起深刻的肠道 导致生物失调的免疫变化。后者会触发一个自我持续的、不适应的反馈循环 这损害了对病毒准种的调节，促进了艾滋病毒-1病毒粒子的肠道持久性，并在 患者亚群，导致CART启动后的次优免疫重建。的目标是 这项研究计划将通过一个独特的合作努力实现，包括三个高度 互补的群体。Saurabh Mehandru博士，Pi，是一位训练有素的胃肠病专家，拥有15年以上的 HIV-1感染领域的经验和对其在粘膜免疫中的影响的几个关键贡献。他 将招募受感染的受试者，获取肠道组织，并沿着 肠道内有艾滋病毒-1病毒储存库(目标1)。Andrea Cerutti博士是世界著名的生物医学专家。 来自健康人和HIV-1感染者的粘膜B细胞。他将研究肠道的免疫球蛋白A反应 HIV-1感染的肠粘膜，重点研究B细胞的个体发育，克隆型结构和细菌的反应性 IgA1和IgA2亚类。他还将定义不平衡的IgA1和IgA2反应对微生物的影响 易位、肠道炎症和艾滋病毒-1复制(目标2)。耶利米·费斯博士是一位国际专家 被公认为微生物组研究的领导者，对该领域做出了几项开创性的贡献。他将会成为 HIV-1诱导的肠道微生物群的改变及其对HIV-1诱导的粘膜IgA扰动的影响。 他还将使用携带HIV-1感染患者或健康对照肠道微生物区系的诺生菌小鼠 测试CART对肠道共生菌的影响，独立于宿主疾病状态(目标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).