IL28B inhibits hepatitis C virus replication through the JAK-STAT pathway.
IL28B inhibits hepatitis C virus replication through the JAK-STAT pathway.
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DOI：
10.1016/j.jhep.2010.11.019
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发表时间：
2011-08
影响因子：
25.7
通讯作者：
Chung, Raymond T.
中科院分区：
文献类型：
--
作者：
Zhang, Leiliang;Jilg, Nikolaus;Shao, Run-Xuan;Lin, Wenyu;Fusco, Dahlene N.;Zhao, Hong;Goto, Kaku;Peng, Lee F.;Chen, Wen-Chi;Chung, Raymond T.
聚乙二醇干扰素(IFN) α联合利巴韦林（RBV）是慢性HCV感染患者的标准治疗方法。然而，它仅在一半的治疗个体中产生持续的病毒学反应（SVR），并伴有明显的副作用。最近，IL28B位点附近的几个单核苷酸多态性（snp），也称为ifn - λ3，被确定为接受PEG-IFN和RBV治疗的患者SVR的有力预测因子。我们试图确定IL28B是否能够抑制HCV复制，并确定IL28B表现出抗HCV活性的途径。利用HCV全长复制子OR6和感染性HCV克隆JFH1和Jc1，我们评估了IL28B对HCV的抗HCV作用，并通过实时PCR、荧光素酶测定和Western blot表征了JAK-STAT通路的关键步骤。最后，我们评估了在JAK-STAT途径抑制剂（如阻断抗体、药理学抑制剂和sirna）存在下IL28B的抗hcv作用。我们发现IL28B以剂量和时间依赖的方式抑制HCV复制。与IFNα一样，IL28B诱导STAT1和STAT2的磷酸化、isre驱动的转录和已知isg的表达。IL28A、IL28B和IL29的抗hcv作用被IL10R2阻断抗体（JAK1/TYK2的药理学抑制剂）和siRNA对IL28R1、STAT1、STAT2和IRF9的抑制作用所消除。我们的数据表明，IL28A、IL28B和IL29通过JAK-STAT通路信号抑制HCV。这些数据提示了新方法在丙型肝炎治疗中的可能应用。
The combination of pegylated interferon (IFN) α and ribavirin (RBV) is standard therapy for patients with chronic HCV infection. However, it produces a sustained virologic response (SVR) in only half of treated individuals and is associated with significant side effects. Recently several single-nucleotide polymorphisms (SNPs) near the IL28B locus, also known as IFNλ3, were identified to be strong predictors of SVR in patients receiving PEG-IFN and RBV. We sought to determine whether IL28B was capable of inhibiting HCV replication and to determine the pathway by which IL28B exhibits anti-HCV activity. Using the full-length HCV replicon OR6 and the infectious HCV clones JFH1 and Jc1, we assessed the anti-HCV effect of IL28B on HCV and characterized the key steps of the JAK-STAT pathway by real time PCR, luciferase assay, and Western blot. Finally, we evaluated the anti-HCV effect of IL28B in the presence of JAK-STAT pathway inhibitors such as blocking antibodies, a pharmacological inhibitor and siRNAs. We found that IL28B inhibits HCV replication in a dose- and time- dependent manner. Like IFNα, IL28B induces the phosphorylation of STAT1 and STAT2, ISRE-driven transcription, and expression of known ISGs. The anti-HCV effects of IL28A, IL28B and IL29 were abrogated by an IL10R2 blocking antibody, a pharmacological inhibitor of JAK1/TYK2, and by siRNA against IL28R1, STAT1, STAT2 and IRF9. Our data demonstrate that IL28A, IL28B and IL29 signal through the JAK-STAT pathway to inhibit HCV. These data suggest possible applications of new approaches in HCV treatment.
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影响因子：
29.4
作者：
McCarthy JJ;Li JH;Thompson A;Suchindran S;Lao XQ;Patel K;Tillmann HL;Muir AJ;McHutchison JG
通讯作者：
McHutchison JG
影响因子：
5
作者：
Dellgren, C.;Gad, H. H.;Hartmann, R.
通讯作者：
Hartmann, R.
影响因子：
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作者：
Ank, Nina;Paludan, Soren R.
通讯作者：
Paludan, Soren R.
影响因子：
29.4
作者：
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通讯作者：
Bochud, Pierre-Yves
影响因子：
4.8
作者：
Zhu H;Butera M;Nelson DR;Liu C
通讯作者：
Liu C