Genotype Differences in Susceptibility and Resistance Development of Hepatitis C Virus to Protease Inhibitors Telaprevir (VX-950) and Danoprevir (ITMN-191)
Genotype Differences in Susceptibility and Resistance Development of Hepatitis C Virus to Protease Inhibitors Telaprevir (VX-950) and Danoprevir (ITMN-191)
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DOI：
10.1002/hep.24172
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发表时间：
2011-04-01
期刊：
影响因子：
13.5
通讯作者：
Simmonds, Peter
中科院分区：
文献类型：
--
作者：
Imhof, Ingrid;Simmonds, Peter
蛋白酶抑制剂（pi）已被证明是干扰素/利巴韦林治疗丙型肝炎病毒（HCV）感染的有效辅助药物。然而，很少有临床或体外数据表明它们对欧洲、中东、非洲和亚洲大部分地区占主导地位的非1型基因型的有效性。将基因型1-6的NS3蛋白酶和NS4A基因插入到JFH克隆中，产生具有复制能力的基因型嵌合体。通过复制和感染性试验确定对PIs的易感性。为了研究耐药性的发展，嵌合体在亚抑制浓度的pi中培养，突变具有表型特征。不同基因型对达诺韦（ITMN-191）和特拉韦（VX-950）的敏感性差异显著。基因型1、4和6的中位抑制浓度（IC50）值为2 ~ 3 nM，比基因型2/3/5 （250 ~ 750 nM）低100倍。特拉匹韦的易感性在4倍范围内变化，基因型1和2最易感，基因型4和5最耐药。在pi中培养基因型1-6诱导了NS3蛋白酶结构域的大量突变，基因型之间的差异很大。通过定点诱变（n = 29）将danoprevir和BILN 2061诱导的突变引入原始克隆（n = 29），都产生了抗性表型，在1/4/6中，最初易感基因型的IC50值增加特别大（1-2 log）。大多数都引入了突变，对繁殖适应性的影响很小或没有影响。结论：不同基因型对PIs的易感性和耐药性存在较大差异。然而，基因型1、4和6对danoprevir的同等敏感性，以及不同基因型之间telaprevir的药效范围比最初设想的更广，这有力地证明了pi可能在基因型1的靶组之外有效使用。(肝脏病学53:1090 2011;1099)
Protease inhibitors (PIs) have proven to be effective adjuncts to interferon/ribavirin treatment of hepatitis C virus (HCV) infections. Little clinical or in vitro data exists, however, on their effectiveness for nontype 1 genotypes that predominate in Europe, the Middle East, Africa, and most of Asia. NS3 protease and NS4A genes from genotypes 1-6 were inserted into the JFH clone to generate replication-competent intergenotype chimeras. Susceptibility to PIs was determined by replication and infectivity assays. To study resistance development, chimeras were cultured in subinhibitory concentrations of PIs and mutations phenotypically characterized. Marked differences in susceptibility of different genotypes to danoprevir (ITMN-191) and telaprevir (VX-950) were observed. Genotypes 1, 4, and 6 showed median inhibitory concentration (IC50) values of 2-3 nM, > 100-fold lower than genotypes 2/3/5 (250-750 nM). Telaprevir susceptibilities varied over a 4-fold range, with genotypes 1 and 2 being most susceptible and genotypes 4 and 5 most resistant. Culture of genotypes 1-6 in PIs induced numerous mutations in the NS3 protease domain, highly variable between genotypes. Introduction of danoprevir and BILN 2061-induced mutations into the original clones by site-directed mutagenesis (n = 29) all conferred resistant phenotypes, with particularly large increases (1-2 log greater IC50 values) in the initially susceptible genotypes 1/4/6. Most introduced mutations and showed little or no effect on replicative fitness. Conclusion: Major differences were found between genotypes in their susceptibility and resistance development to PIs. However, equal sensitivities of genotypes 1, 4, and 6 to danoprevir and a broader efficacy range of telaprevir between genotypes than initially conceptualized provide strong evidence that PIs might be effectively used beyond their genotype 1 target group. (HEPATOLOGY 2011;53:1090-1099)