A profiling study of a newly developed HCVcc strain PR63cc's sensitivity to direct‐acting antivirals
A profiling study of a newly developed HCVcc strain PR63cc's sensitivity to direct‐acting antivirals
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DOI：
10.1016/j.antiviral.2016.12.009
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发表时间：
2017-03
影响因子：
7.6
通讯作者：
Wanyin Tao;Tianyu Gan;Jie Lu;Jin Zhong
中科院分区：
文献类型：
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作者：
Wanyin Tao;Tianyu Gan;Jie Lu;Jin Zhong
直接作用抗病毒药物（DAAs）的发展显著改善了丙型肝炎病毒（HCV）的治疗。然而，在现实世界中基于daa的治疗中，耐药性仍然是一个潜在的问题。我们之前直接从临床分离株中开发了一种新的全长基因型2a HCVcc克隆PR63cc。在本研究中，我们比较了PR63cc和JFH1对12种不同daa的敏感性，其中大多数daa已经在临床使用或处于临床后期开发阶段。对于NS5B抑制剂，PR63cc和JFH1对核苷/核苷酸类似物索非布韦和2 ' - c -甲基腺苷的敏感性相当，而PR63cc对非核苷抑制剂奈斯布韦的敏感性是JFH1的4倍。有趣的是，PR63cc和JFH1都对达沙布韦完全耐药，达沙布韦有效地抑制了1b基因型HCV复制子的复制。对于NS5A抑制剂，PR63cc对ombitasvir和velpatasvir的敏感性与JFH1相当，但对daclatasvir和ledipasvir的耐药程度远高于JFH1，主要原因是NS5A氨基酸残基31处的蛋氨酸。对于NS3抑制剂，PR63cc对simeprevir、grazoprevir、asunaprevir和paritaprevir的敏感性普遍低于JFH1。NS3残基67处的丝氨酸被鉴定为asunaprevir的耐药相关变体（RAV）。最后，我们发现PR63cc比JFH1对asunaprevir/daclatasvir联合治疗更耐药。总之，我们的研究系统地分析了一种新的HCVcc菌株的DAA敏感性，并确定了关键的RAVs。这些结果不仅对监测当前DAA治疗的耐药突变的出现很重要，而且对开发下一代DAA也很有价值。
The development of direct-acting antivirals (DAAs) has significantly improved hepatitis C virus (HCV) treatment. However, drug resistance remains a potential concern in the real-world DAA-based therapies. We previously developed a novel full-length genotype 2a HCVcc clone PR63cc directly from clinical isolates. Here in this study, we compared the sensitivity of PR63cc and JFH1 to 12 different DAAs most of which are either already in clinical use or in the late clinical development phase. For NS5B inhibitors, PR63cc and JFH1 displayed comparable sensitivity to nucleoside/nucleotide analogues sofosbuvir and 2′-C-methyladenosine, while PR63cc was 4-fold more sensitive than JFH1 to nesbuvir, a non-nucleoside inhibitor. Interestingly, PR63cc and JFH1 were both completely resistant to dasabuvir which efficiently inhibited the replication of genotype 1b HCV replicon. For NS5A inhibitors, while PR63cc was as sensitive as JFH1 to ombitasvir and velpatasvir, it was much more resistant than JFH1 to daclatasvir and ledipasvir, which was mainly due to methionine at amino acid residue 31 of NS5A. For NS3 inhibitors, PR63cc was generally less sensitive than JFH1 to simeprevir, grazoprevir, asunaprevir and paritaprevir. Serine at residue 67 of NS3 was identified to be a resistance-associated variant (RAV) for asunaprevir. Finally, we showed that PR63cc was more resistant than JFH1 to the asunaprevir/daclatasvir combination treatment. In summary, our study systemically analyzed the DAA sensitivity of a new HCVcc strain and identified critical RAVs. These results are not only important for monitoring the emergence of drug-resistant mutations of current DAA therapies, but also valuable for developing next-generation DAAs.