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

项目概要 肠道微生物群、粘膜免疫细胞和 HIV-1 病毒粒子通过密切的关系影响彼此的功能。 以及决定感染者疾病结果的多方面相互作用。在这个多 PI 提案中， 我们将检验这一中心假设：HIV-1 感染会严重破坏粘膜免疫 系统，在开始联合抗逆转录病毒治疗（cART）后该问题并未解决。由 HIV-1 中断微生物群和宿主免疫系统之间的关键信号，引起严重的肠道损伤 导致菌群失调的免疫改变。后者会触发自我延续、适应不良的反馈循环 损害病毒准种的调节，促进 HIV-1 病毒粒子在肠道中的持久存在，并且 部分患者在开始 cART 后导致免疫重建不理想。的目标 该研究计划将通过三个高度重视的独特合作努力来实现 互补的群体。 Saurabh Mehandru 博士，PI，是一位训练有素的胃肠病学家，拥有超过 15 年的临床经验 HIV-1感染领域的经验及其对粘膜免疫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，并分析肠道和全身免疫群体 肠道内存在 HIV-1 储存库（目标 1）。联合首席研究员 Andrea Cerutti 博士是世界著名的生物学专家 来自健康人和 HIV-1 感染者的粘膜 B 细胞。他将研究肠道 IgA 反应 HIV-1 感染的肠道粘膜，重点关注 B 细胞个体发育、克隆型结构和细菌反应性 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 HIV-1 复制（目标 2）。 Jeremiah Faith 博士，联合首席研究员，是一位国际 微生物组研究领域公认的领导者，对该领域做出了多项开创性贡献。他将表征 HIV-1 诱导的肠道微生物组改变及其对 HIV-1 诱导的粘膜 IgA 扰动的影响。 他还将使用携带 HIV-1 感染者或健康对照者肠道微生物群的无菌小鼠 测试 cART 对肠道共生菌的影响，与宿主疾病状态无关（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).