Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes
Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes
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DOI：
10.1038/ncomms6699
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发表时间：
2014-12-01
影响因子：
16.6
通讯作者：
Hartmann, Rune
中科院分区：
文献类型：
--
作者：
Terczynska-Dyla, Ewa;Bibert, Stephanie;Hartmann, Rune
丙型肝炎病毒（HCV）感染是世界范围内慢性肝病、肝硬化和肝细胞癌的主要原因。HCV的自发清除和治疗诱导清除都取决于干扰素- λ基因座的遗传变异，但到目前为止还没有明确的因果关系。在这里，我们证明了IFN lambda 4蛋白中的氨基酸取代将70位的脯氨酸改变为丝氨酸（P70S），从而大大改变了其抗病毒活性。与编码完全激活的IFN lambda 4-P70变体的患者相比，携带受损IFN lambda 4-S70变体的患者表现出较低的干扰素刺激基因（ISG）表达水平，更好的治疗反应率和更好的自发清除率。总之，这些数据提供了支持活性IFN lambda 4蛋白作为肝脏高ISG表达的驱动因素以及HCV清除率低的原因的证据。
Hepatitis C virus (HCV) infections are the major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide. Both spontaneous and treatment-induced clearance of HCV depend on genetic variation within the interferon-lambda locus, but until now no clear causal relationship has been established. Here we demonstrate that an amino-acid substitution in the IFN lambda 4 protein changing a proline at position 70 to a serine (P70S) substantially alters its antiviral activity. Patients harbouring the impaired IFN lambda 4-S70 variant display lower interferon-stimulated gene (ISG) expression levels, better treatment response rates and better spontaneous clearance rates, compared with patients coding for the fully active IFN lambda 4-P70 variant. Altogether, these data provide evidence supporting a role for the active IFN lambda 4 protein as the driver of high hepatic ISG expression as well as the cause of poor HCV clearance.