Activation of anti-hepatitis C virus responses via Toll-like receptor 7
Activation of anti-hepatitis C virus responses via Toll-like receptor 7
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DOI：
10.1073/pnas.0510801103
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发表时间：
2006-02-07
影响因子：
11.1
通讯作者：
Carson, DA
中科院分区：
文献类型：
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作者：
Lee, J;Wu, CCN;Carson, DA
IFN-α用于抑制慢性感染患者中丙型肝炎病毒（HCV）的复制，部分成功。在这里，我们提出的证据表明，Toll样受体7（TLR 7）的配体可以诱导抗HCV免疫不仅通过IFN诱导，但也通过IFINI独立的机制。携带HCV复制子的人肝细胞系Huh-7表达TLR 7，并且受体的激活诱导包括IFN调节因子-7在内的几种抗病毒基因。肌苷一磷酸脱氢酶的抑制剂增强了IFN依赖性和非依赖性的抗病毒作用。Huh-7细胞长期暴露于TLR 7配体[SM 360320（9-苄基-8-羟基-2-（2-甲氧基-乙氧基）腺嘌呤）]，单独或与肌苷单磷酸脱氢酶抑制剂联合使用，可剂量依赖性地降低HCV水平。肝脏的免疫组织化学分析表明，TLR 7在正常或HCV感染者的肝细胞中表达。由于TLR 7激动剂可以通过I型IFN和独立于IFN阻止HCV感染，因此它们可以被认为是慢性HCV感染的替代治疗，特别是在IFN-α抗性患者中。
IFN-alpha is used to suppress the replication of hepatitis C virus (HCV) in chronically infected patients with partial success. Here we present evidence showing that a ligand of Toll-like receptor 7 (TLR7) can induce anti-HCV immunity not only by IFN induction, but also through an IFINI-independent mechanism. Human hepatocyte line Huh-7 carrying an HCV replicon expressed TLR7, and activation of the receptor induced several antiviral genes including IFN regulatory factor-7. Inhibitors of the enzyme inosine monophosphate dehydrogenase augmented both IFN-dependent and -independent antiviral effect. Prolonged exposure of Huh-7 cells to a TLR7 ligand [SM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine)], alone or in combination with an inosine monophosphate dehydrogenase inhibitor, reduced HCV levels dose dependently. Immunolhistochemical analysis of livers shows that TLR7 is expressed in hepatocytes of normal or HCV-infected people. Because TLR7 agonists can impede HCV infection both via type I IFN and independently of IFN, they may be considered as an alternative treatment of chronic HCV infection, especially in IFN-a-resistant patients.