Impact of novel NS5A resistance-associated substitutions of hepatitis C virus detected in treatment-experienced patients
Impact of novel NS5A resistance-associated substitutions of hepatitis C virus detected in treatment-experienced patients
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DOI：
10.1038/s41598-019-42114-z
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发表时间：
2019-04-05
影响因子：
4.6
通讯作者：
Watanabe, Mamoru
中科院分区：
文献类型：
--
作者：
Nitta, Sayuri;Asahina, Yasuhiro;Watanabe, Mamoru
丙型肝炎病毒（HCV）NS 5A区域的耐药相关置换（RAS）会损害NS 5A抑制剂的疗效。在这项研究中，我们评估了在治疗失败的患者中观察到的新RAS的特征，A92 K和P32缺失（P32 del），以及这些RAS病毒对各种抗HCV试剂的敏感性，通过使用基于JFH-1的重组HCV与来自基因型1b Con 1株（JFH 1/5ACon 1）的NS 5A。我们将A92 K或P32 del单独或与Q24 K、L28 M、R30 Q或L31 F组合引入JFH 1/5ACon 1的NS 5A中。携带R30 Q/A92 K的病毒表现出高的细胞外核心抗原和感染性滴度，而携带RAS的其他病毒表现出低的复制水平和感染性滴度。所有携带A92 K或P32 de 1的病毒对ledipasvir、velpatasvir和elbasvir明显耐药。有趣的是，具有R30 Q/A92 K的病毒比不具有RAS的病毒更易受grazoprevir的影响。所有病毒对利巴韦林和索非布韦的敏感性相似。总之，组合RAS R30 Q/A92 K增强病毒产生，而其他RAS损害病毒复制。A92 K和P32 del都赋予甚至对第二代NS 5A抑制剂的严重抗性。然而，这些病毒对grazoprevir、ribavirin和sofosbuvir敏感。因此，与这些试剂的组合方案可以根除携带A92 K或P32 del的病毒。
Resistance-associated substitutions (RASs) of hepatitis C virus (HCV) in the NS5A region impair the efficacy of NS5A inhibitors. In this study, we evaluated the characteristics of the novel RASs observed in treatment-failure patients, A92K and a deletion at P32 (P32del), and the susceptibility of viruses with these RASs to various anti-HCV reagents by using JFH-1 based recombinant HCV with NS5A from a genotype 1b Con1 strain (JFH1/5ACon1). We introduced A92K or P32del solely or in combination with Q24K, L28M, R30Q or L31F into the NS5A of JFH1/5ACon1. Viruses harboring R30Q/A92K showed high extracellular core antigens and infectivity titers, whereas the other viruses with RASs showed low replication levels and infectivity titers. All the viruses with A92K or P32de1 were markedly resistant to ledipasvir, velpatasvir and elbasvir. Interestingly, viruses with R30Q/A92K were more susceptible to grazoprevir than viruses without RAS. All the viruses had a similar susceptibility to ribavirin and sofosbuvir. In conclusion, combination RASs R30Q/A92K enhanced virus production whereas other RASs impaired virus replication. Both A92K and P32del conferred severe resistance even to second generation NS5A inhibitors. However, these viruses were susceptible to grazoprevir, ribavirin and sofosbuvir. Thus, combination regimens with these reagents may eradicate viruses harboring A92K or P32del.