Hepatitis C Virus Frameshift/Alternate Reading Frame Protein Suppresses Interferon Responses Mediated by Pattern Recognition Receptor Retinoic-Acid-Inducible Gene-I.
Hepatitis C Virus Frameshift/Alternate Reading Frame Protein Suppresses Interferon Responses Mediated by Pattern Recognition Receptor Retinoic-Acid-Inducible Gene-I.
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DOI：
10.1371/journal.pone.0158419
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Ojcius DM
中科院分区：
文献类型：
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作者：
Park SB;Seronello S;Mayer W;Ojcius DM
丙型肝炎病毒（HCV）主动逃避宿主干扰素（IFN）的反应，但其机制尚不完全清楚。在这项研究中，我们提出的证据表明，丙型肝炎病毒的因素，有助于抑制视黄酸诱导基因-I（RIG-I）介导的IFN诱导。HCV-2/+1框移码/交替阅读框蛋白（F/ARFP）在Huh 7肝癌细胞中的表达抑制HCV RNA病原相关分子模式（PAMP）和poly（IC）刺激的I型IFN应答。这种抑制作用的发生与其他HCV因子无关;干扰素刺激基因TNFα、IFN-λ1和IFN-λ2/3的激活同样受到HCV F/ARFP的抑制。在全长HCV序列（JFH 1基因型2a株）中进行点突变，在编码F/ARFP的-2/+1阅读框中引入提前终止密码子，同时保留原始阅读框，这增强了HCV对IFNα和IFNβ的诱导。F/ARFP突变对IFN应答的增强作用在已经具有缺陷RIG-I的Huh7.5细胞中以及通过降低Huh 7细胞中的RIG-I表达而减弱。此外，通过反式互补将F/ARFP加回抑制了F/ARFP突变体中的IFN诱导。另一方面，F/ARFP突变体对外源性IFNα不耐药。最后，HCV感染的人类肝脏样品显示出显着的F/ARFP抗体反应性，与HCV未感染的对照肝脏相比。因此，HCV F/ARFP可能与其他病毒因子合作，通过RIG-I信号通路抑制I型和III型IFN诱导。本研究确定了HCV模式识别受体调节的一种新机制，并提示了HCV交替阅读框架在宿主先天免疫调节中的生物学功能。
Hepatitis C virus (HCV) actively evades host interferon (IFN) responses but the mechanisms of how it does so are not completely understood. In this study, we present evidence for an HCV factor that contributes to the suppression of retinoic-acid-inducible gene-I (RIG-I)-mediated IFN induction. Expression of frameshift/alternate reading frame protein (F/ARFP) from HCV -2/+1 frame in Huh7 hepatoma cells suppressed type I IFN responses stimulated by HCV RNA pathogen-associated molecular pattern (PAMP) and poly(IC). The suppression occurred independently of other HCV factors; and activation of interferon stimulated genes, TNFα, IFN-λ1, and IFN-λ2/3 was likewise suppressed by HCV F/ARFP. Point mutations in the full-length HCV sequence (JFH1 genotype 2a strain) were made to introduce premature termination codons in the -2/+1 reading frame coding for F/ARFP while preserving the original reading frame, which enhanced IFNα and IFNβ induction by HCV. The potentiation of IFN response by the F/ARFP mutations was diminished in Huh7.5 cells, which already have a defective RIG-I, and by decreasing RIG-I expression in Huh7 cells. Furthermore, adding F/ARFP back via trans-complementation suppressed IFN induction in the F/ARFP mutant. The F/ARFP mutants, on the other hand, were not resistant to exogenous IFNα. Finally, HCV-infected human liver samples showed significant F/ARFP antibody reactivity, compared to HCV-uninfected control livers. Therefore, HCV F/ARFP likely cooperates with other viral factors to suppress type I and III IFN induction occurring through the RIG-I signaling pathway. This study identifies a novel mechanism of pattern recognition receptor modulation by HCV and suggests a biological function of the HCV alternate reading frame in the modulation of host innate immunity.