Neuronal apoptosis induced by HIV-1 Tat protein and TNF-α:: potentiation of neurotoxicity mediated by oxidative stress and implications for HIV-1 dementia
Neuronal apoptosis induced by HIV-1 Tat protein and TNF-α:: potentiation of neurotoxicity mediated by oxidative stress and implications for HIV-1 dementia
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DOI：
10.3109/13550289809114529
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发表时间：
1998-06-01
影响因子：
3.2
通讯作者：
Gabuzda, D
中科院分区：
文献类型：
--
作者：
Shi, B;Raina, J;Gabuzda, D
在患有痴呆症的艾滋病患者的大脑中已经证实了神经元和非神经元细胞的凋亡。先前的研究表明，凋亡刺激可能是可溶性因子。已经提出了几种导致 HIV-1 感染中神经元凋亡的候选因子，包括 HIV-1 Tat 蛋白和 TNF-α。体内导致艾滋病患者大脑神经细胞凋亡的机制可能涉及一种以上促凋亡因子的联合作用。在这项研究中，我们研究了与单独暴露于任一因子相比，将原代人类神经元暴露于 HIV-1 Tat 和 TNF-α 的组合是否可以增强神经元凋亡的诱导。研究表明，TNF-α 可通过增加氧化应激的机制，增强 HIV-1 Tat 对神经元凋亡的诱导。抗氧化剂抑制但并没有完全消除 Tat 诱导的神经元凋亡，这表明其他机制也可能参与其中。这些发现表明，可溶性 HIV-1 Tat 和 TNF-α 可能在中枢神经系统 HIV-1 感染诱导的神经元凋亡中发挥作用，特别是当两者联合存在时。我们的研究结果进一步表明，促凋亡因子的组合可能增强艾滋病患者大脑中神经元凋亡诱导的一种机制是通过增加氧化应激。了解氧化应激和导致中枢神经系统 HIV-1 感染中细胞凋亡的其他机制的作用可能会促进新治疗策略的开发，以预防神经元细胞死亡并改善 AIDS 患者的神经功能。
Apoptosis of neurons and non-neuronal cells has been demonstrated in the brain of AIDS patients with dementia. Previous studies suggest that the apoptotic stimuli are likely to be soluble factors. Several candidates for the soluble factors that lead to neuronal apoptosis in HIV-1 infection have been proposed, including the HIV-1 Tat protein and TNF-alpha. The mechanisms that lead to neuronal apoptosis in the brain of AIDS patients in vivo, may involve the combined effects of more than one pro-apoptotic factor. In this study, we examine whether exposure of primary human neurons to the combination of HIV-1 Tat and TNF-alpha can potentiate the induction of neuronal apoptosis compared with exposure to either factor alone. TNF-alpha was shown to potentiate the induction of neuronal apoptosis by HIV-1 Tat via a mechanism that involves increased oxidative stress. Antioxidants inhibited, but did not completely abolish the induction of neuronal apoptosis by Tat, suggesting that other mechanisms are also likely to be involved. These findings suggest that soluble HIV-1 Tat and TNF-alpha may play a role in neuronal apoptosis induced by HIV-1 infection of the CNS, particularly when present in combination. Our findings further suggest that one mechanism whereby combinations of pro-apoptotic factors may potentiate the induction of neuronal apoptosis in the brain of AIDS patients is by increasing oxidative stress. Understanding the role of oxidative stress and other mechanisms that lead to apoptosis in HIV-1 infection of the CNS may advance the development of new therapeutic strategies to prevent neuronal cell death and improve neurologic function in AIDS patients.