Gamma Delta T cell and microbial modulation to target chronic SIV-associated inflammation

项目总结 肠道功能障碍、生物失调和残留炎症是导致高发病率的主要因素。 艾滋病病毒携带者的代谢、心血管、肾脏和肝脏疾病等合并症 抗逆转录病毒疗法(ART)。然而，肠道功能障碍过程中的免疫机制和 ART长期抑制病毒的环境中的持续性炎症仍然知之甚少。我们 最近在非人类灵长类动物艾滋病毒模型中与ART一起报告了以下初步解决方案 ART早期循环渗漏的肠道生物标志物与肠道伽玛病的IL-17/IL-22功能失调 德尔塔(γδ)T细胞与肠上皮屏障损伤的复发和全身性 在长期的艺术创作过程中的炎症。此外，肠道Vδ2T细胞频率与丢失显著相关 在长期的抗逆转录病毒治疗过程中，特定的肠道微生物种类。在此基础上，我们建议检验假设 γδT细胞中IL-17/IL-22途径的特异性失调，特别是Vδ2亚群，有助于 肠道上皮屏障的破坏，导致微生物移位(MT)和全身炎症 慢性治疗的艾滋病毒感染。在这里，我们建议评估Vδ2γδT细胞在修复和维持中的作用 通过直接的体内干预来维持肠道内环境的稳定。我们将评估体内Vδ2T刺激的效果 长期ART治疗中IEBD、MT和炎症的扩大通过治疗抑制SIV感染 氨基双膦酸类药物唑来膦酸盐(ZOL)与IL-2和IL-15细胞因子联合应用。第二，我们 建议用微生物检验慢性SIV+ART期间肠道微生物群的调节假说 补充剂联合体内V-δ-2T细胞刺激对改善肠道屏障有协同作用 功能。我们将实施粪便微生物移植(FMT)，并辅以抗炎细菌 使用/不使用ZOL治疗以评估全身炎症标志物和肠道免疫正常化的物种 仅FMT与有免疫调节的FMT的功能。最后，我们将确定γδT 在长期治疗SIV感染期间，细胞和微生物群调节肠上皮细胞的动态平衡。我们会 纵向评估肠道IL-17/IL-22产生细胞的转录和功能特征 在精确定时的肠道活检和体外共培养试验中评估上皮屏障功能以鉴定新的 涉及的细胞/分子机制。通过探索联合免疫/微生物组的有益效果 对上皮屏障保护功能和全身炎症的调节，本研究将具有关键意义 为继续发展目标的组合办法开辟新途径的影响 艾滋病毒携带者的肠病和慢性炎症。

PROJECT SUMMARY Gut dysfunction, dysbiosis, and residual inflammation are major factors contributing to the high prevalence of comorbidities such as metabolic, cardiovascular, kidney, and liver diseases in people living with HIV under antiretroviral therapy (ART). However, the immune mechanisms underlying the process of gut dysfunction and persistent inflammation in the setting of long-term viral suppression with ART remain poorly understood. We have recently reported in the nonhuman primate model of HIV with ART that following initial resolution of circulating leaky gut biomarkers during early ART, dysregulation of IL-17/IL-22 functions of intestinal Gamma delta (γδ) T cells are correlated with resurgence of intestinal epithelial barrier damage (IEBD) and systemic inflammation during long-term ART. Further, intestinal Vδ2T cell frequencies significantly correlated with the loss of specific gut microbial species during long-term ART. Based on this, we propose to test the hypothesis that specific dysregulation of the IL-17/IL-22 pathway in γδT cells, particularly the Vδ2 subset, contributes to breakdown of the gut epithelial barrier, resulting in microbial translocation (MT) and systemic inflammation during chronic treated HIV infection. Here, we propose to assess the role of Vδ2 γδT cells in the repair and maintenance of gut homeostasis through a direct in vivo intervention. We will evaluate the effect of in vivo Vδ2T-stimulation and expansion on IEBD, MT, and inflammation in long-term ART suppressed SIV-infection via treatment with the aminobisphosphonate drug, Zoledronate (ZOL) in combination with IL-2 and IL-15 cytokines. Second, we propose to test the hypothesis that modulation of gut microbiome during chronic SIV+ART with microbial supplementation combined with in vivo Vδ2T cell stimulation will have a synergistic effect on improving gut barrier functions. We will administer fecal microbial transplant (FMT) supplemented with anti-inflammatory bacterial species, with/without ZOL treatment to assess normalization of systemic inflammatory markers and gut immune functions in FMT-only vs. FMT with immunomodulation. Finally, we will determine the mechanisms by which γδT cells and microbiome modulate intestinal epithelial homeostasis during long-term treated SIV infection. We will longitudinally assess the transcriptional and functional signatures of intestinal IL-17/IL-22 producing cells and evaluate epithelial barrier functions in precisely timed gut biopsies and in vitro coculture assays to identify novel cellular/molecular mechanisms involved. By exploring the beneficial effects of combined immune/microbiome modulation on epithelial barrier-protective function and systemic inflammation, this study will have the critical impact of opening new avenues for the continued development of combinatorial approaches to target enteropathy and chronic inflammation in people living with HIV.