ROS-Induced Mitochondrial Dysfunction in CD4 T Cells from ART-Controlled People Living with HIV.
ROS-Induced Mitochondrial Dysfunction in CD4 T Cells from ART-Controlled People Living with HIV.
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DOI：
10.3390/v15051061
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发表时间：
2023-04-26
期刊：
影响因子：
--
通讯作者：
Yao ZQ
中科院分区：
文献类型：
--
作者：
Schank M;Zhao J;Wang L;Nguyen LNT;Zhang Y;Wu XY;Zhang J;Jiang Y;Ning S;El Gazzar M;Moorman JP;Yao ZQ
我们以前已经证明了抗逆转录病毒治疗（ART）控制的HIV感染者（PLWH）的衰老CD 4 T细胞中的线粒体功能障碍。然而，CD 4 T细胞在PLWH中发生线粒体功能障碍的潜在机制仍不清楚。在这项研究中，我们试图阐明ART控制的PLWH中CD 4 T细胞线粒体受损的机制。我们首先评估了活性氧（ROS）的水平，并且我们观察到与健康受试者（HS）相比，来自PLWH的CD 4 T细胞中细胞和线粒体ROS水平显著增加。此外，我们观察到PLWH CD 4 T细胞中负责抗氧化防御（超氧化物歧化酶1，SOD 1）和ROS介导的DNA损伤修复（脱嘌呤/脱嘧啶核酸内切酶1，APE 1）的蛋白质水平显着降低。重要的是，CRISPR/Cas9介导的HS CD 4 T细胞中SOD 1或APE 1的敲低证实了它们在通过p53介导的途径维持正常线粒体呼吸中的作用。在来自PLWH的CD 4 T细胞中重建SOD 1或APE 1成功地挽救了线粒体功能，如Seahorse分析所证明的。这些结果表明，ROS诱导线粒体功能障碍，导致过早的T细胞老化通过失调的SOD 1和APE 1在潜伏的HIV感染。
We have previously demonstrated mitochondrial dysfunction in aging CD4 T cells from antiretroviral therapy (ART)-controlled people living with HIV (PLWH). However, the underlying mechanisms by which CD4 T cells develop mitochondrial dysfunction in PLWH remain unclear. In this study, we sought to elucidate the mechanism(s) of CD4 T cell mitochondrial compromise in ART-controlled PLWH. We first assessed the levels of reactive oxygen species (ROS), and we observed significantly increased cellular and mitochondrial ROS levels in CD4 T cells from PLWH compared to healthy subjects (HS). Furthermore, we observed a significant reduction in the levels of proteins responsible for antioxidant defense (superoxide dismutase 1, SOD1) and ROS-mediated DNA damage repair (apurinic/apyrimidinic endonuclease 1, APE1) in CD4 T cells from PLWH. Importantly, CRISPR/Cas9-mediated knockdown of SOD1 or APE1 in CD4 T cells from HS confirmed their roles in maintaining normal mitochondrial respiration via a p53-mediated pathway. Reconstitution of SOD1 or APE1 in CD4 T cells from PLWH successfully rescued mitochondrial function as evidenced by Seahorse analysis. These results indicate that ROS induces mitochondrial dysfunction, leading to premature T cell aging via dysregulation of SOD1 and APE1 during latent HIV infection.
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