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

项目摘要 肠道功能障碍、微生态失调和残余炎症是导致高患病率的主要因素。 合并症，如代谢，心血管，肾脏和肝脏疾病的艾滋病毒感染者， 抗逆转录病毒疗法（ART）。然而，肠道功能障碍过程的免疫机制和 在ART长期病毒抑制的情况下，持续性炎症仍然知之甚少。我们 最近报道，在非人灵长类动物HIV模型中， 早期ART期间循环漏肠生物标志物，肠γ-淀粉酶的IL-17/IL-22功能失调， δ（γδ）T细胞与肠上皮屏障损伤（IEBD）和系统性 此外，肠道Vδ 2 T细胞频率与长期ART期间的炎症损失显著相关。 在长期ART期间，特定肠道微生物物种的数量。基于此，我们建议检验以下假设： γδT细胞中IL-17/IL-22通路的特异性失调，特别是Vδ2亚群，有助于 肠道上皮屏障的破坏，导致微生物易位（MT）和全身性炎症， 慢性治疗的艾滋病毒感染。在这里，我们建议评估Vδ2 γδT细胞在修复和维护中的作用。 通过直接的体内干预来维持肠道内稳态。我们将评估体内Vδ 2 T刺激的效果， 和扩大IEBD，MT和炎症在长期ART抑制SIV感染，通过治疗 氨基二膦酸盐药物唑来膦酸盐（ZOL）与IL-2和IL-15细胞因子的组合。二是 建议检验以下假设：在慢性SIV+ART期间， 补充与体内Vδ 2 T细胞刺激组合将对改善肠道屏障具有协同作用 功能协调发展的我们将进行粪便微生物移植（FMT），并补充抗炎细菌 种属，有/无ZOL治疗，以评估全身炎症标志物和肠道免疫功能的正常化 在仅FMT与具有免疫调节的FMT中的功能。最后，我们将确定γδT 细胞和微生物组在长期治疗的SIV感染期间调节肠上皮的稳态。我们将 纵向评估肠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价上皮屏障功能，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， 调节上皮屏障保护功能和全身炎症，这项研究将具有关键性的意义。 开辟新途径，继续发展综合办法， 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.