Enhancing mitochondrial metabolism to rescue Immune dysfunction in immune non responders to ART

增强线粒体代谢以挽救对 ART 免疫无反应者的免疫功能障碍

基本信息

批准号：
10316832
负责人：
Souheil Antoine Younes
金额：
$ 20.73万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10316832
关键词：
Enhancing mitochondrial metabolism rescue Immune

项目摘要

The introduction of combination antiretroviral therapy (ART) has had major impact on morbidity and mortality of HIV-1 infected persons. Nonetheless, despite effective control of HIV replication with ART, a minority of treated persons fails to increase CD4+T cell counts to levels observed in uninfected subjects 1,2. These immune failure or immune non-responder (INR) subjects remain at greater risk for morbidity and mortality than are immune responders (IR) in whom CD4+T cell count is restored 3,4. Despite low CD4+T cell numbers, increased frequency of cycling CD4+T- cells is a hallmark of poor immune reconstitution in these persons1,2. In addition, high levels of inflammation are characteristic 1,5,6 and an exhaustion/senescence phenotype of CD4+T cells has been reported 5,6. Importantly, the INR phenotype is more common in older individuals 7,8. Based on our preliminary data, we hypothesize that mitochondrial dysfunction underlies the INR phenotype. We proposed a model where INR subjects fail to restore CD4+T cells as a consequence of defective mitochondrial fitness that affects negatively Treg survival and function. This leads to uncontrolled cell cycling, immune exhaustion, and increased cell death. The working hypothesis of this proposal in based on our preliminary data that will appear soon in the Journal of Clinical Investigation (Ref. 37). First, we showed that in all persons, cycling CD4+T cells are enriched for cells having a phenotype of regulatory T cells (Tregs). Second, sorted cycling CD4+T cells of INRs do not complete cell cycle or proliferate in vitro in contrast to findings among IR or healthy controls that do. Third, we found cycling Tregs of INR were dysfunctional by transcriptomic and flow cytometry analyses and this was linked to low CD4+T cell counts and to impaired mitochondrial activity. Fourth, we showed that exposure of cycling CD4+T cells and Tregs from INR to IL-15 corrects mitochondrial dysfunction and improves T cell proliferation by induction of the master regulator of mitochondrial biogenesis, the peroxisome proliferator- activated receptor gamma coactivator 1-alpha (PGC1). Thus, we hypothesize that enhancing mitochondrial biogenesis might correct exhaustion and senescence that are characteristics of CD4+ T cells in INRs. PGC1 can be induced through at least three distinct pathways: 1) activation of the peroxisome proliferator-activated receptors (PPAR, PPAR, PPAR) nuclear transcription factors regulating genes implicated in mitochondrial biogenesis and bioenergy9,10, 2) activation of AMP-activated protein kinase (AMPK) by agents such as Resveratrol and the AMP analog, 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR ) or 3) activation of the mammalian target of rapamycin (mTOR) (See Figure 2). We hypothesize that mitochondrial dysfunction drives immune failure in INRs as a consequence of diminished PGC1 expression that is correctible through exposure to IL-15 and/or combinations of PGC1 inducers (PPAR/AMPK/IL-15).

联合抗逆转录病毒疗法（ART）的引入对发病率产生了重大影响尽管有效控制了 HIV 复制，但 HIV-1 感染者的死亡率仍然很高。通过 ART，少数接受治疗的人未能将 CD4+T 细胞计数增加到观察到的水平未感染的受试者 1,2。这些免疫失败或免疫无反应 (INR) 受试者仍处于与使用 CD4+T 细胞的免疫应答者 (IR) 相比，发病和死亡的风险更大尽管 CD4+T 细胞数量较低，但 CD4+T- 循环频率增加了3,4。细胞是这些人免疫重建不良的标志1,2。炎症是其特征 1,5,6 并且 CD4+T 细胞的耗竭/衰老表型据报道 5,6 重要的是，INR 表型在老年人中更为常见 7,8。根据我们的初步数据，我们认为线粒体功能障碍是导致我们提出了一个模型，其中 INR 受试者无法恢复 CD4+T 细胞。线粒体健康缺陷对 Treg 存活和功能产生负面影响的结果。这会导致细胞周期失控、免疫衰竭和细胞死亡增加。该提案的工作假设基于我们即将发布的初步数据《临床研究杂志》（参考文献 37）首先，我们发现在所有人中，CD4+T 循环。富集具有调节性 T 细胞 (Treg) 表型的细胞其次，分选。与研究结果相反，INR 的循环 CD4+T 细胞在体外无法完成细胞周期或增殖第三，我们发现 INR 循环 Tregs 功能失调。转录组学和流式细胞术分析，这与低 CD4+T 细胞计数和第四，我们发现循环 CD4+T 细胞的暴露和线粒体活性受损。从 INR 到 IL-15 的 Tregs 可通过以下方式纠正线粒体功能障碍并改善 T 细胞增殖：诱导线粒体生物发生的主要调节剂，过氧化物酶体增殖剂- 激活受体 γ 共激活剂 1-α (PGC1α)。线粒体生物发生可能会纠正疲劳和衰老 PGC1α 中 CD4+ T 细胞的特征可以通过至少三种不同的方式诱导。途径：1) 激活过氧化物酶体增殖物激活受体（PPARα、PPARα、 PPAR）核转录因子调节与线粒体生物发生有关的基因和生物能源9,10, 2) 通过以下物质激活 AMP 激活蛋白激酶 (AMPK) 白藜芦醇和 AMP 类似物 5-氨基咪唑-4-甲酰胺核糖核苷酸 (AICAR ) 或 3) 哺乳动物雷帕霉素靶标 (mTOR) 的激活（见图 2）。由于 INR 减少，线粒体功能障碍导致免疫失败 PGC1 表达可通过暴露于 IL-15 和/或以下物质的组合来纠正 PGC1α 诱导剂 (PPAR/AMPK/IL-15)。