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

• 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
• 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

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).

采用抗逆转录病毒综合疗法对发病率产生了重大影响 和HIV-1感染者的死亡率。尽管如此，尽管有效地控制了艾滋病毒的复制， 在ART中，少数接受治疗的人未能将CD 4 +T细胞计数增加到 未受感染的受试者1，2.这些免疫失败或免疫无反应（INR）受试者仍处于 发病率和死亡率的风险高于免疫应答者（IR），其中CD 4 +T细胞 计数恢复3，4。尽管CD 4 +T细胞数量较低，但循环CD 4 +T细胞的频率增加， 细胞是这些人免疫重建不良的标志1，2。此外，高水平的 炎症是特征性1、5、6，且CD 4 +T细胞耗竭/衰老表型 报告5，6。重要的是，INR表型在老年人中更常见7，8。 基于我们的初步数据，我们假设线粒体功能障碍是导致 INR表型。我们提出了一个模型，其中INR受试者不能恢复CD 4 +T细胞作为一个免疫缺陷。 这是线粒体适应性缺陷的结果，对Treg的存活和功能产生负面影响。 这导致细胞周期不受控制，免疫衰竭和细胞死亡增加。 这项建议的工作假设是基于我们的初步数据，这些数据将很快出现在 临床研究杂志（参考文献37）。首先，我们发现，在所有人中， 富集细胞中具有调节性T细胞（T细胞）表型的细胞。二、排序 与研究结果相反，INR的循环CD 4 +T细胞在体外不完成细胞周期或增殖 在IR或健康对照组中。第三，我们发现INR的循环T细胞功能失调， 转录组学和流式细胞术分析，这与低CD 4 +T细胞计数和 线粒体活性受损第四，我们发现暴露于循环CD 4 +T细胞和 从INR到IL-15的TCRP通过以下途径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因子，过氧化物酶体增殖物， 活化受体γ辅激活因子1-α（PGC 1 α）。因此，我们假设， 线粒体生物合成可能会纠正疲劳和衰老， INR中CD 4 + T细胞的特征。PGC 1 β可以通过至少三种不同的途径诱导， 途径：1）过氧化物酶体增殖物激活受体（PPARs，PPARs， 核转录因子调节线粒体生物发生相关基因， 生物能9，10，2）通过试剂如 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)雷帕霉素的哺乳动物靶（mTOR）的活化（参见图2）。我们假设 线粒体功能障碍导致INR中的免疫失败， PGC 1表达可通过暴露于IL-15和/或以下物质的组合来纠正 PGC 1 β诱导剂（PPAR/AMPK/IL-15）。