Expression of hepatitis C virus proteins inhibits signal transduction through the Jak-STAT pathway
Expression of hepatitis C virus proteins inhibits signal transduction through the Jak-STAT pathway
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DOI：
10.1128/jvi.73.10.8469-8475.1999
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发表时间：
1999-10-01
影响因子：
5.4
通讯作者：
Blum, HE
中科院分区：
文献类型：
--
作者：
Heim, MH;Moradpour, D;Blum, HE
丙型肝炎病毒（HCV）感染是世界范围内肝脏疾病的主要原因。α干扰素（IFN-cw）治疗慢性丙型肝炎仅在10%至20%的患者中产生持续反应。丙型肝炎病毒持续存在的机制和发病机制知之甚少。我们建立了连续的人类细胞系，允许严格调控表达的整个HCV开放阅读框架下的四环素反应启动子的控制。使用这种体外系统，我们分析了HCV蛋白对IFN诱导的细胞内信号传导的影响。HCV蛋白在这些细胞中的表达强烈抑制IFN-α诱导的通过Jak-STAT途径的信号转导。抑制发生在STAT酪氨酸磷酸化的下游。Jak-STAT途径的抑制不限于IFN-α诱导的信号传导，但也通过Stat 3在白血病抑制因子诱导的信号传导中观察到。相比之下，肿瘤坏死因子α诱导的转录因子NF-κ B的活化不受影响。HCV通过Jak-STAT途径干扰IFN-α诱导的信号传导可能导致在大多数患者中观察到的IFN-α治疗耐药，并可能代表HCV的一般逃逸策略，导致病毒持续存在和慢性肝病的发病机制。
Hepatitis C virus (HCV) infection is a leading cause of liver disease worldwide. Alpha interferon (IFN-cw) therapy of chronic hepatitis C leads to a sustained response in 10 to 20% of patients only. The mechanisms of viral persistence and the pathogenesis of hepatitis C are poorly understood. We established continuous human cell lines, allowing the tightly regulated expression of the entire HCV open reading frame under the control of a tetracycline-responsive promoter. Using this in vitro system, we analyzed the effect of HCV proteins on IFN-induced intracellular signaling. Expression of HCV proteins in these cells strongly inhibited IFN-alpha-induced signal transduction through the Jak-STAT pathway. Inhibition occurred downstream of STAT tyrosine phosphorylation. Inhibition of the Jak-STAT pathway was not restricted to IFN-alpha-induced signaling but was observed in leukemia inhibitory factor-induced signaling through Stat3 as well. By contrast, tumor necrosis factor alpha-induced activation of the transcription factor NF-kappa B was not affected. Interference of HCV with IFN-alpha-induced signaling through the Jak-STAT pathway could contribute to the resistance to IFN-alpha therapy observed in the majority of patients and may represent a general escape strategy of HCV contributing to viral persistence and pathogenesis of chronic liver disease.