Effects of Resistance-Associated NS5A Mutations in Hepatitis C Virus on Viral Production and Susceptibility to Antiviral Reagents.
Effects of Resistance-Associated NS5A Mutations in Hepatitis C Virus on Viral Production and Susceptibility to Antiviral Reagents.
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DOI：
10.1038/srep34652
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发表时间：
2016-10-05
影响因子：
4.6
通讯作者：
Kato T
中科院分区：
文献类型：
--
作者：
Nitta S;Asahina Y;Matsuda M;Yamada N;Sugiyama R;Masaki T;Suzuki R;Kato N;Watanabe M;Wakita T;Kato T
丙型肝炎病毒（HCV）的直接作用抗病毒药物（DAA）具有强效抗HCV作用，但可能引起耐药相关变异体（RAV）。在这项研究中，我们评估了这些RAV的特点，并探讨了有效的抗HCV试剂使用重组HCV与NS 5A基因型1b株。我们将JFH 1的NS 5A替换为Con 1的NS 5A（JFH 1/5ACon 1），并单独或组合引入已知的NS 5A抑制剂抗性突变（L31 M、L31 V、L31 I和Y 93 H）。还研究了抗HCV试剂的敏感性。具有Y 93 H的RAV表现出高的细胞外核心抗原水平和感染性滴度。具有任何单一突变的变体显示对NS 5A抑制剂的轻度至中度抗性，而在L31和Y 93处具有双重突变的变体显示严重抗性。变异株对干扰素（IFN）-α、IFN-λ1、IFN-λ3和利巴韦林的敏感性相似。与JFH 1/5ACon 1相比，具有Y 93 H突变的变体对蛋白酶抑制剂更敏感。总之，体外分析表明Y 93 H突变增强了感染性病毒的产生，表明具有该突变的RAV在繁殖中的优势。然而，这些RAV对蛋白酶抑制剂敏感。因此，包括这些试剂的治疗方案是根除这些RAV的有希望的手段。
Direct-acting antivirals (DAAs) for hepatitis C virus (HCV) have potent anti-HCV effects but may provoke resistance-associated variants (RAVs). In this study, we assessed the characteristics of these RAVs and explored efficacious anti-HCV reagents using recombinant HCV with NS5A from a genotype 1b strain. We replaced the NS5A of JFH1 with that of Con1 (JFH1/5ACon1) and introduced known NS5A inhibitor resistance mutations (L31M, L31V, L31I and Y93H) individually or in combination. Susceptibilities against anti-HCV reagents were also investigated. RAVs with Y93H exhibited high extracellular core antigen levels and infectivity titers. Variants with any single mutation showed mild to moderate resistance against NS5A inhibitors, whereas variants with double mutations at both L31 and Y93 showed severe resistance. The variants with mutations exhibited similar levels of susceptibility to interferon (IFN)-α, IFN-λ1, IFN-λ3 and Ribavirin. Variants with the Y93H mutation were more sensitive to protease inhibitors compared with JFH1/5ACon1. In conclusion, the in vitro analysis indicated that the Y93H mutation enhanced infectious virus production, suggesting advantages in the propagation of RAVs with this mutation. However, these RAVs were susceptible to protease inhibitors. Thus, a therapeutic regimen that includes these reagents is a promising means to eradicate these RAVs.
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影响因子：
14.8
作者：
Kato, Takanobu;Date, Tomoko;Wakita, Takaji
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