Silencing of USP18 potentiates the antiviral activity of interferon against hepatitis C virus infection
Silencing of USP18 potentiates the antiviral activity of interferon against hepatitis C virus infection
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DOI：
10.1053/j.gastro.2006.08.043
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发表时间：
2006-11-01
期刊：
影响因子：
29.4
通讯作者：
McGilvray, Ian D.
中科院分区：
文献类型：
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作者：
Randall, Glenn;Chen, Limin;McGilvray, Ian D.
背景与目的：调节宿主先天免疫应答是抑制丙型肝炎病毒（HCV）复制的一种有吸引力的手段。先前已经确定干扰素敏感基因（ISG）15蛋白酶USP 18的表达在对干扰素（IFN）-α治疗无反应的患者的肝活检标本中增加，我们假设USP 18可能阻碍IFN抑制HCV复制的能力。研究方法：使用复制完整病毒生命周期的HCV复制体外模型检查USP 18在IFN抗病毒活性中的作用。使用小抑制RNA（siPNAs）特异性沉默USP 18，并测量HCV复制和感染性病毒产生对IFN-α的剂量反应。结果如下：人细胞中USP 18的siRNA敲除持续增强IFN抑制HCV-RNA复制和感染性病毒颗粒产生的能力，增强因子为1-2 log（10）。USP 18敲低也导致了许多细胞变化，与对IFN的敏感性增加一致。降低USP 18表达导致响应于外源性IFN-α的细胞蛋白ISG化增加，信号转导子的酪氨酸磷酸化和转录激活（STAT 1）延长，以及IFN刺激的基因表达的普遍增强。结论：这些数据表明，USP 18调节抗HCV I型IFN应答，并且是治疗HCV感染的可能治疗靶点。
Background & Aims: Modulation of the host innate immune response is an attractive means of inhibiting hepatitis C virus (HCV) replication. Having previously determined that expression of the interferon-sensitive gene (ISG)15 protease USP18 is increased in the liver biopsy specimens of patients who do not respond to interferon (IFN)-alfa therapy, we hypothesized that USP18 might hinder the ability of IFN to inhibit HCV replication. Methods: The role of USP18 in IFN antiviral activity was examined using an in vitro model of HCV replication that reproduces the full viral life cycle. USP18 was silenced specifically using small inhibitory RNAs (siPNAs), and the dose response of HCV replication and infectious virus production to IFN-alfa was measured. Results: The siRNA knockdown of USP18 in human cells consistently potentiated the ability of IFN to inhibit HCV-RNA replication and infectious virus particle production by a factor of 1-2 log(10). USP18 knockdown also resulted in a number of cellular changes consistent with increased sensitivity to IFN. Decreasing USP18 expression led to increased cellular protein ISGylation in response to exogenous IFN-alfa, prolonged tyrosine phosphorylation of signal transducer and activation of transcription (STAT1), and a general enhancement of IFN-stimulated gene expression. Conclusions: These data suggest that USP18 modulates the anti-HCV type I IFN response, and is a possible therapeutic target for the treatment of HCV infection.