氧化损伤在HIV相关神经认知损害中的作用

摘要

目的 研究由活性氧诱导的DNA氧化损伤在感染了艾滋病毒的患者中枢神经系统组织中的积累.方法 利用感染人类免疫缺陷病毒(human immunodeficiency virus,HIV-1)的患者的尸检脑组织的额叶皮质来分析HIV-1亚型,采用免疫荧光染色、定量聚合酶链式反应(polymerase chain reaction,PCR)和PCR克隆测序分析脑细胞中核和线粒体DNA损伤.结果 中枢神经系统感染HIV会导致大脑细胞中核和线粒体DNA基因组的损伤.对HIV相关的神经认知功能障碍患者的尸检皮质组织进行检测可以发现有高水平的核和线粒体DNA 8-氧鸟嘌呤(8-hydroxyguanine,8-oxoG)损伤.在HIV相关的神经认知障碍的一个亚型脑组织中有逐渐增加的线粒体DNA突变和缺失,这与病情已经得到控制的情况大为不同.结论 在HIV相关的神经认知障碍患者的中枢神经系统中高水平的氧化损伤对HIV引发神经细胞和胶质细胞的神经免疫和凋亡发挥了重要作用.%Objective Oxidative stress has been suggested to play a key role in the neuropathogenesis of HIV infection. HIV proteins (gpl20, Tat) , and proinflammatory cytokines can trigger the production of reactive oxygen species (ROS) , resulting in DNA and RNA lesions. Among all the lesions induced by ROS, one of the most frequently occurred lesions in DNA and RNA is 8-hydroxydeoxyguanosine (8-oxoG). Here, we report accumulated DNA oxidative damage induced by ROS in the central nervous system (CNS) in tissue from neuro-AIDS patients. Methods The frontal cortex of autopsy tissue from HIV-1 infected patients was adopted for analysis for HIV-1 subtype, nuclear and mitochondria] DNA lesions by immunofluorescence staining, qPCR and sequencing of PCR cloning. Results This study provides evidence that HIV infection in the CNS leads to nuclear and mitochondrial genomic DNA damage in the brain. High level of nuclear and mtDNA 8-oxoG damage were identified in the cortex autopsy tissue of HIV-associated neurocognitive disorder ( HAND) patients. Increased accumulation of mtDNA mutations and depletion occurs in brain tissue in a subset of HAND cases, and is significantly different from that observed in control cases. Conclusion These findings suggest that higher level of ROS in the CNS of HAND patients would contribute to the HIV induced neuro-inflammation and apoptosis of neuronal and glial cells.