Hepatitis C virus core protein up-regulates anergy-related genes and a new set of genes, which affects T cell homeostasis
Hepatitis C virus core protein up-regulates anergy-related genes and a new set of genes, which affects T cell homeostasis
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DOI：
10.1189/jlb.0507335
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发表时间：
2007-11-01
影响因子：
5.5
通讯作者：
Garcia-Cozar, F.
中科院分区：
文献类型：
--
作者：
Dominguez-Villar, M.;Munoz-Suano, A.;Garcia-Cozar, F.
丙型肝炎病毒（HCV）感染是慢性肝炎的主要病因，可导致肝硬化和肝癌。病毒引起的免疫功能障碍被认为是病毒持续存在的原因。先前的结果表明，稳定表达HCV核心蛋白的CD 4 Jurkat细胞显示NFAT转录因子的活化增加和IL-2启动子活性受损，以模拟克隆无反应性的方式影响细胞内信号传导途径。我们先前已经表明，NFAT激活转录程序，从而导致免疫耐受。在目前的工作中，我们设计了表达HCV核心的慢病毒载体，以分析在HCV核心诱导的无能的初始阶段展开的事件。我们发现，最初被描述为在小鼠中被离子霉素诱导的无能上调的基因在人类中也被上调，不仅被离子霉素上调，而且被HCV核心表达上调。我们还表明，HCV核心是足以导致NFAT核转位和细胞周期进程的放缓，并使用全基因组微阵列，我们确定了新的基因表达HCV核心的Jurkat细胞上调。我们的研究结果的相关性是由HCV慢性感染患者的CD 4 T细胞中HCV的存在而引起的。
Hepatitis C virus (HCV) infection is the main cause for chronic hepatitis, leading to cirrhosis and hepatic carcinoma. Virally induced immune dysfunction has been called as the cause for viral persistence. Previous results demonstrate that CD4 Jurkat cells stably expressing the HCV core protein show an increased activation of NFAT transcription factor and an impaired IL-2 promoter activity, affecting intracellular signaling pathways in a manner that mimics clonal anergy. We had shown previously that NFAT activates a transcriptional program, ensuing in immunological tolerance. In the present work, we have engineered lentiviral vectors expressing the HCV core to analyze the events, which unfold in the initial phase of HCV core-induced anergy. We show that genes initially described to he up-regulated by ionomycin-induced anergy in mice are also up-regulated in humans, not only by ionomycin but also by HCV core expression. We also show that HCV core is sufficient to cause NFAT nuclear translocation and a slow-down in cell-cycle progression, and using whole genome microarrays, we identify novel genes up-regulated in Jurkat cells expressing HCV core. The relevance of our results is higblighted by the presence of HCV in CD4 T cells from HCV chronically infected patients.