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Abstract：
Resistance-associated substitutions (RASs) of hepatitis C virus (HCV) affect the efficacy of direct-acting antivirals (DAAs). In this study, we aimed to clarify the susceptibility of the coexistence of nonstructural (NS) 5A Q24K/L28M/R30Q (or R30E)/A92K RASs, which were observed in patients with DAAs re-treatment failure and to consider new therapeutic agents. We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir. The Q24K/L28M/R30E/A92K RASs was 816.3 times more resistant to pibrentasvir than the Q24K/L28M/R30Q/A92K RASs. Furthermore, a combination of pibrentasvir and sofosbuvir showed therapeutic efficacy against these RASs. Combination regimens may eradicate HCV with NS5A Q24K/L28M/R30E/A92K RASs.
摘要：
丙型肝炎病毒（HCV）的抗性相关替换（RAS）影响直接作用的抗病毒药物（DAA）的功效。在这项研究中,我们旨在阐明非结构（NS）5AQ24K/L28M/R30Q（或R30E）/A92KRAS共存的敏感性，在DAA再治疗失败的患者中观察到，并考虑新的治疗药物。我们使用亚基因组复制子系统，其中HCV基因型1B菌株1B-4被电穿孔到源自HuH-7细胞的OR6c细胞中（野生型[WT]）。我们将WT基因转换为NS5AQ24K/L28M/R30Q/A92K或Q24/L28K/R30E/A92K。与WT相比,Q24K/L28M/R30Q/A92KRAS对daclatasvir具有36,000倍的抗性，440,000倍耐ledipasvir，6300倍耐velpatasvir，3100倍耐elbasvir，和1.8倍耐pibrentasvir。与WT相比,Q24K/L28M/R30E/A92KRAS对daclatasvir和ledipasvir的抗性为640,000倍，15万倍耐velpatasvir，44,000倍耐elbasvir，抗pibrentasvir1500倍。Q24K/L28M/R30E/A92KRAS对pibrentasvir的抗性是Q24K/L28M/R30Q/A92KRAS的816.3倍。此外，pibrentasvir和sofosbuvir的组合对这些RAS具有治疗效果.联合方案可以用NS5AQ24K/L28M/R30E/A92KRAS根除HCV。
