Rapid Emergence of Telaprevir Resistant Hepatitis C Virus Strain from Wildtype Clone In Vivo
Rapid Emergence of Telaprevir Resistant Hepatitis C Virus Strain from Wildtype Clone In Vivo
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DOI：
10.1002/hep.24460
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发表时间：
2011-09-01
期刊：
影响因子：
13.5
通讯作者：
Chayama, Kazuaki
中科院分区：
文献类型：
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作者：
Hiraga, Nobuttiko;Imamura, Michio;Chayama, Kazuaki
替拉维韦是丙型肝炎病毒NS3-4A蛋白水解酶的有效抑制剂。然而，在治疗过程中出现耐药菌株是一个严重的问题，耐药菌株对干扰素(干扰素)的敏感性，以及体内出现突变菌株的细节尚不清楚。我们之前利用人肝细胞嵌合小鼠建立了丙型肝炎病毒感染模型。利用该系统，我们利用超深测序技术对突变体的生物学特性和出现方式进行了研究。给嵌合小鼠注射从一名患者获得的血清样本，该患者在Telapvir单一治疗期间出现病毒突破，并对耐药性突变进行了强烈选择(A156F[92.6%])。感染耐药株(A156F[99.9%])的小鼠只出现低水平的病毒血症，通过干扰素治疗成功地消除了病毒。正如在患者中观察到的那样，在病毒症小鼠中使用telapvir单一疗法取得了突破，选择了对telapvir具有耐药性的突变(例如，V36A的高频率[52.2%])。小鼠肝内注射丙型肝炎病毒基因1b克隆KT-9，在NS3区有或没有引入耐药突变A156S，并用替瑞韦治疗。与野生型菌株相比，感染A156S菌株的小鼠出现了较低水平的病毒血症，但对替拉维韦治疗表现出强烈的耐药性。尽管注射野生型丙型肝炎病毒的小鼠在治疗开始时显示出病毒血症的迅速下降，但在开始治疗2周后出现了高频率(11%)的耐药NS3V36A变异体。结论：利用深度测序技术和基因工程丙型肝炎病毒感染系统，我们证明了体内耐药丙型肝炎病毒的快速出现是由丙型肝炎病毒野生型毒株的突变引起的。(《肝病》2011；54：781-788)
Telaprevir is a potent inhibitor of hepatitis C virus (HCV) NS3-4A protease. However, the emergence of drug-resistant strains during therapy is a serious problem, and the susceptibility of resistant strains to interferon (IFN), as well as the details of the emergence of mutant strains in vivo, is not known. We previously established an infectious model of HCV using human hepatocyte chimeric mice. Using this system we investigated the biological properties and mode of emergence of mutants by ultra-deep sequencing technology. Chimeric mice were injected with serum samples obtained from a patient who had developed viral breakthrough during telaprevir monotherapy with strong selection for resistance mutations (A156F [92.6%]). Mice infected with the resistant strain (A156F [99.9%]) developed only low-level viremia and the virus was successfully eliminated with interferon therapy. As observed in patients, telaprevir monotherapy in viremic mice resulted in breakthrough, with selection for mutations that confer resistance to telaprevir (e.g., a high frequency of V36A [52.2%]). Mice were injected intrahepatically with HCV genotype 1b clone KT-9 with or without an introduced resistance mutation, A156S, in the NS3 region, and treated with telaprevir. Mice infected with the A156S strain developed lower-level viremia compared to the wildtype strain but showed strong resistance to telaprevir treatment. Although mice injected with wildtype HCV showed a rapid decline in viremia at the beginning of therapy, a high frequency (11%) of telaprevir-resistant NS3 V36A variants emerged 2 weeks after the start of treatment. Conclusion: Using deep sequencing technology and a genetically engineered HCV infection system, we showed that the rapid emergence of telaprevir-resistant HCV was induced by mutation from the wildtype strain of HCV in vivo. (HEPATOLOGY 2011;54:781-788)