Activation of the Oxidative Stress Pathway by HIV-1 Vpr Leads to Induction of Hypoxia-inducible Factor 1α Expression
Activation of the Oxidative Stress Pathway by HIV-1 Vpr Leads to Induction of Hypoxia-inducible Factor 1α Expression
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DOI：
10.1074/jbc.m809266200
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发表时间：
2009-04-24
影响因子：
4.8
通讯作者：
Sawaya, Bassel E.
中科院分区：
文献类型：
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作者：
Deshmane, Satish L.;Mukerjee, Ruma;Sawaya, Bassel E.
对人类免疫缺陷病毒、1 型 (HIV) 相关痴呆患者的脑组织和脑脊液中氧化应激生物标志物的检测表明，应激途径参与了艾滋病的神经发病机制。尽管氧化应激对艾滋病神经发病机制和负责氧化应激的HIV-1蛋白的生物学重要性仍有待阐明，但我们的研究结果表明，缺氧诱导因子1（HIF-1）在HIV-1感染后被激活，并且在患有痴呆的艾滋病患者的脑细胞中升高。 HIF-1 是一种对氧有反应的转录因子。在缺氧条件下，HIF-1 α 变得稳定并易位到细胞核，在细胞核中与芳基烃受体核易位蛋白形成二聚体并调节基因转录。 HIF-1 的激活也可以由 HIV-1 辅助蛋白 Vpr 介导。此外，包括活性氧在内的细胞成分有助于诱导 HIF-1 α。我们的结果表明，Vpr 通过增加 H2O2 的产生来诱导活性氧，这有助于 HIF-1 α 的积累。有趣的是，HIF-1α水平的增加通过HIF-1与HIV-1长末端重复序列的关联刺激了HIV-1基因转录。这些观察结果表明，HIF-1 α 和 Vpr 之间存在正反馈相互作用，并且通过激活 HIF-1 诱导氧化应激，Vpr 可以诱导 HIV-1 基因表达并失调多种宿主细胞途径。
The detection of biomarkers of oxidative stress in brain tissue and cerebrospinal fluid of patients with human immunodeficiency virus, type 1 (HIV)-associated dementia indicates the involvement of stress pathways in the neuropathogenesis of AIDS. Although the biological importance of oxidative stress on events involved in AIDS neuropathogenesis and the HIV-1 proteins responsible for oxidative stress remain to be elucidated, our results point to the activation of hypoxia-inducible factor 1 (HIF-1) upon HIV-1 infection and its elevation in brain cells of AIDS patients with dementia. HIF-1 is a transcription factor that is responsive to oxygen. Under hypoxic conditions, HIF-1 alpha becomes stable and translocates to the nucleus where it dimerizes with aryl hydrocarbon receptor nuclear translocator and modulates gene transcription. Activation of HIF-1 can also be mediated by the HIV-1 accessory protein Vpr. In addition, cellular components, including reactive oxygen species, contribute to the induction of HIF-1 alpha. Our results show that Vpr induces reactive oxygen species by increasing H2O2 production, which can contribute to HIF-1 alpha accumulation. Interestingly, increased levels of HIF-1 alpha stimulated HIV-1 gene transcription through HIF-1 association with HIV-1 long terminal repeat. These observations point to the existence of a positive feedback interplay between HIF-1 alpha and Vpr and that, by inducing oxidative stress via activation of HIF-1, Vpr can induce HIV-1 gene expression and dysregulate multiple host cellular pathways.