HCV Infection Selectively Impairs Type I but Not Type III IFN Signaling
HCV Infection Selectively Impairs Type I but Not Type III IFN Signaling
复制标题
DOI：
10.1016/j.ajpath.2013.10.005
复制
发表时间：
2014-01-01
影响因子：
6
通讯作者：
Dash, Srikanta
中科院分区：
文献类型：
--
作者：
Chandra, Partha K.;Bao, Lili;Dash, Srikanta
开发了稳定且持续的丙型肝炎病毒（HCV）复制细胞培养模型，以检查使用干扰素-α（IFN-alpha）、IFN-lambda和病毒唑（RBV）长期治疗期间病毒复制的清除情况。持续HCV感染的细胞培养物对IFN-α +RBV联合治疗表现出受损的抗病毒应答，而IFN-λ治疗产生了清除HCV复制的强烈和持续的抗病毒应答。HCV在持续感染细胞中的复制诱导慢性内质网（ER）应激和自噬反应，选择性下调I型IFN-α受体1链的功能，但不下调II型（IFN-γ）或III型（IFN-λ）IFN受体。IFN-α受体-1的下调导致JAK-STAT信号传导缺陷、STAT磷酸化受损和STAT核转位受损。此外，由于核苷转运蛋白ENT 1和CNT 1的表达减少，HCV复制损害RBV摄取。使用化学抑制剂或siRNA沉默ER应激和自噬应答通过IFN-α +RBV组合治疗附加地抑制HCV复制并诱导病毒清除。这些结果表明，HCV诱导ER应激，自噬反应选择性地损害I型（而不是III型）IFN信号传导，这解释了为什么IFN-λ（而不是IFN-α）产生持续的抗HCV抗病毒反应。结果还表明，ER应激和自噬反应的抑制克服了与HCV感染相关的IFN-α +RBV抗性机制。
A stable and persistent Hepatitis C virus (HCV) replication cell culture model was developed to examine clearance of viral replication during long-term treatment using interferon-alpha (IFN-alpha), IFN-lambda, and ribavirin (RBV). Persistently HCV-infected cell culture exhibited an impaired antiviral response to IFN-alpha+RBV combination treatment, whereas IFN-lambda treatment produced a strong and sustained antiviral response that cleared HCV replication. HCV replication in persistently infected cells induced chronic endoplasmic reticulum (ER) stress and an autophagy response that selectively down-regulated the functional IFN-alpha receptor-1 chain of type I, but not type II (IFN-gamma) or type III (IFN-lambda) IFN receptors. Down-regulation of IFN-alpha receptor-1 resulted in defective JAK-STAT signaling, impaired STAT phosphorylation, and impaired nuclear translocation of STAT. Furthermore, HCV replication impaired RBV uptake, because of reduced expression of the nucleoside transporters ENT1 and CNT1. Silencing ER stress and the autophagy response using chemical inhibitors or siRNA additively inhibited HCV replication and induced viral clearance by the IFN-alpha+RBV combination treatment. These results indicate that HCV induces ER stress and that the autophagy response selectively impairs type I (but not type III) IFN signaling, which explains why IFN-lambda (but not IFN-alpha) produced a sustained antiviral response against HCV. The results also indicate that inhibition of ER stress and of the autophagy response overcomes IFN-alpha+RBV resistance mechanisms associated with HCV infection.