Hyper-responsiveness to stimulation of human immunodeficiency virus-infected CD4+ T cells requires Nef and Tat virus gene products and results from higher NFAT, NF-κB, and AP-1 induction
Hyper-responsiveness to stimulation of human immunodeficiency virus-infected CD4+ T cells requires Nef and Tat virus gene products and results from higher NFAT, NF-κB, and AP-1 induction
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DOI：
10.1074/jbc.m407477200
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发表时间：
2004-09-17
影响因子：
4.8
通讯作者：
Tremblay, MJ
中科院分区：
文献类型：
--
作者：
Fortin, JF;Barat, C;Tremblay, MJ
免疫过度激活的慢性状态是人类免疫缺陷病毒1型（HIV-1）感染的一个特征。对HIV-1调节T细胞激活状态的分子机制的研究表明，Nef和Tat都可以改变T细胞的激活。然而，绝大多数数据是从编码单一病毒蛋白的载体进行的实验中获得的。我们证明完全感染HIV-1的人CD4(+) T淋巴细胞感染导致白细胞介素-2启动子的高反应性。在参与不同信号转导途径的各种药物刺激下，观察到hiv -1感染的T细胞的超敏反应。用重组热稳定抗原编码HIV-1进行的实验表明，病毒感染的细胞是具有增强应答的细胞。Nef和Tat都参与了病毒介导的对白细胞介素-2启动子活性的增强作用。有趣的是，Nef似乎主要通过活化T细胞核因子（NFAT）的过度活化起作用，而Tat则以NFAT独立的方式起作用。移动性转移实验表明，hiv -1相关的人类T细胞启动刺激导致更大程度的转录因子被认为是T细胞激活的重要参与者，即NFAT， NF-kappaB和AP-1。当HIV-1感染更自然的细胞库，即原发CD4(+) T淋巴细胞时，也建立了高反应状态。考虑到HIV-1的生命周期受到T细胞信号机制的严格调控，激活主要病毒库的启动代表了这种逆转录病毒可以为其繁殖和维持创造理想的细胞微环境的一种手段。
A chronic state of immune hyperactivation is a feature of human immunodeficiency virus type-1 (HIV-1) infection. Studies on the molecular mechanisms by which HIV-1 can modulate the activation state of T cells indicate that both Nef and Tat can alter T cell activation. However, the vast majority of data has been obtained from experiments performed with vectors encoding a single virus protein. We demonstrate that infection of human CD4(+) T lymphocytes with fully infectious HIV-1 leads to a hyper-responsiveness of the interleukin-2 promoter. Hypersensitivity in HIV-1-infected T cells was observed upon stimulation with various agents that are engaging different signal transduction pathways. Experiments performed with recombinant heat stable antigen-encoding HIV-1 indicated that the virus-infected cells are the cells with an enhanced response. Both Nef and Tat are involved in this virus-mediated enhancing effect on interleukin-2 promoter activity. Interestingly, whereas Nef seems to be acting mainly through hyperactivation of nuclear factor of activated T cells (NFAT), Tat acts in an NFAT-independent manner. Mobility shift experiments demonstrated that the HIV-1-associated priming of human T cells for stimulation results in a greater induction of transcription factors recognized as essential players in T cell activation, i.e. NFAT, NF-kappaB, and AP-1. A hyper-responsive state was also established upon HIV-1 infection of a more natural cellular reservoir, i.e. primary CD4(+) T lymphocytes. Considering that the HIV-1 life cycle is tightly regulated by the T cell signaling machinery, the priming for activation of a major viral reservoir represents a means by which this retrovirus can create an ideal cellular microenvironment for its propagation and maintenance.