Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
AIDS Res Hum Retroviruses. 2021 Mar;37(3):224-232. doi: 10.1089/AID.2020.0176. Epub 2020 Nov 11.
Despite the advent of antiretroviral therapy, people living with HIV suffer from a range of infectious and noninfectious pulmonary complications. HIV impairs antioxidant defenses and innate immune function of the alveolar macrophage by diminishing granulocyte macrophage-colony stimulating factor (GM-CSF) signaling. Since GM-CSF may be linked to mitochondria, we sought to determine the effects of HIV on GM-CSF receptor expression and alveolar macrophage mitochondrial function. At an academic medical center, studies were completed on alveolar macrophages isolated from both wild-type and HIV transgenic (HIV Tg) rats and human subjects with and without HIV. Primary macrophages were plated and evaluated for expression of GM-CSF receptor beta, phagocytic index, and mitochondrial function in the presence and absence of GM-CSF treatment. GM-CSF receptor expression and mitochondrial function were impaired in macrophages isolated from HIV Tg rats, and treatment with GM-CSF restored GM-CSF receptor expression and mitochondrial function. GM-CSF treatment of HIV Tg rats also increased alveolar macrophage levels of the mitochondrial proteins voltage-dependent anion-selective channel 1 (VDAC) and glucose-regulated protein 75 (Grp75). Similar to the HIV Tg rat model, impairments in mitochondrial bioenergetics were confirmed in alveolar macrophages isolated from human subjects with HIV. HIV-associated impairments in alveolar macrophage mitochondrial bioenergetics likely contribute to innate immune dysfunction in HIV infection, and GM-CSF treatment may offer a novel therapeutic strategy for mitigating these deleterious effects.
尽管抗逆转录病毒疗法已经问世，但艾滋病毒感染者仍会遭受一系列感染和非感染性肺部并发症的困扰。艾滋病毒通过减少粒细胞巨噬细胞集落刺激因子（GM-CSF）信号，损害肺泡巨噬细胞的抗氧化防御和先天免疫功能。由于 GM-CSF 可能与线粒体有关，我们试图确定 HIV 对 GM-CSF 受体表达和肺泡巨噬细胞线粒体功能的影响。在一家学术医疗中心，对来自野生型和 HIV 转基因（HIV Tg）大鼠以及有和没有 HIV 的人类受试者的肺泡巨噬细胞进行了研究。将原代巨噬细胞铺板，并在存在和不存在 GM-CSF 处理的情况下评估 GM-CSF 受体β、吞噬指数和线粒体功能的表达。从 HIV Tg 大鼠分离的巨噬细胞中 GM-CSF 受体表达和线粒体功能受损，GM-CSF 治疗恢复了 GM-CSF 受体表达和线粒体功能。GM-CSF 治疗 HIV Tg 大鼠还增加了肺泡巨噬细胞中电压依赖性阴离子选择性通道 1（VDAC）和葡萄糖调节蛋白 75（Grp75）等线粒体蛋白的水平。与 HIV Tg 大鼠模型相似，从人类 HIV 感染者分离的肺泡巨噬细胞中也证实了线粒体生物能量学的损害。HIV 相关的肺泡巨噬细胞线粒体生物能量学损伤可能导致 HIV 感染中的先天免疫功能障碍，GM-CSF 治疗可能为减轻这些有害影响提供一种新的治疗策略。
