Natural prevalence of NS5A polymorphisms in subjects infected with hepatitis C virus genotype 3 and their effects on the antiviral activity of NS5A inhibitors
Natural prevalence of NS5A polymorphisms in subjects infected with hepatitis C virus genotype 3 and their effects on the antiviral activity of NS5A inhibitors
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DOI：
10.1016/j.jcv.2012.12.020
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发表时间：
2013-05-01
影响因子：
8.8
通讯作者：
McPhee, Fiona
中科院分区：
文献类型：
--
作者：
Hernandez, Dennis;Zhou, Nannan;McPhee, Fiona
背景：丙型肝炎病毒(丙型肝炎病毒)NS5A复制复合体抑制物(RCIS)在体外表现出对1型(GT1)的皮摩尔抗病毒活性。这导致GT1患者的丙型肝炎病毒RNA迅速而强劲地下降。目的：检测自然发生的HCVGT3NS5A多态与两个临床研究中的NS5A RCI(Daclatasvir[DCV]和GS-5885)的表型。研究设计：对96例来自北美、欧洲和澳大利亚的未接受治疗的丙型肝炎病毒GT3患者的NS5A区域进行测定。在GT3人群中发现了GT1 DCV耐药相关变异(RAV)，变异(及其频率)包括28M/V(1%)、30A/K/S/T/V(10%)、31L/M(1%)、E92A(1%)和Y93H(8.3%)。使用通用序列产生JFH1/3a-NS5A杂交复制子，并用于评估对NS5A RCIS的易感性。DCV对JFH1/3a-NS5A的抗性(EC50=0.52 nM)强于GS-5885(EC50=141 nM)。DCV对JFH1/3a-NS5A-M28V(EC50=0.006 nM)、A30V(EC50=0.012 nM)和E92A(EC50=0.004 nM)的敏感性增加，而NS5A-A30K和-Y93H型变异体对DCV(EC50值分别为23 nM和1120 nM)和GS-5885(EC50值分别为1770 nM和4300 nM)的敏感性降低。这些NS5A RCIS在临床上发挥作用的有效性可能取决于哪种抑制剂与其他抗病毒药物联合使用。(C)2013爱思唯尔B.V.保留所有权利。
Background: Hepatitis C virus (HCV) NS5A replication complex inhibitors (RCIs) have been shown to exhibit picomolar antiviral activity against genotype 1 (GT1) in vitro. This has translated into rapid and robust declines in HCV RNA in GT1 patients. Less is known about the susceptibility of other genotypes such as GT3 to inhibition by NS5A RCIs.Objectives: To detect and phenotype naturally occurring HCVGT3 NS5A polymorphisms against two NS5A RCIs (daclatasvir [DCV] and GS-5885) currently in clinical development.Study design: The NS5A region from 96 HCV GT3 treatment-naive patients spanning North America, Europe and Australia was determined.Results: Phylogenetic analysis revealed a broad distribution with no significant geographic clustering. GT1 DCV resistance-associated variants (RAVs) were observed in GT3 subjects; variants (and their frequencies) included 28M/V (1%), 30A/K/S/T/V (10%), 31L/M (1%), E92A (1%) and Y93H (8.3%). A consensus sequence was used to generate a JFH1/3a-NS5A hybrid replicon and employed to assess susceptibility to NS5A RCIs. Against JFH1/3a-NS5A, DCV was more potent (EC50 = 0.52 nM) than GS-5885 (EC50 = 141 nM). DCV sensitivity was increased against JFH1/3a-NS5A-M28V (EC50 = 0.006 nM), A30V (EC50 = 0.012 nM), and E92A (EC50 = 0.004 nM) while the NS5A-A30K and -Y93H variants exhibited reduced sensitivity to DCV (EC50 values of 23 nM and 1120 nM, respectively) and to GS-5885 (EC50 values of 1770 nM and 4300 nM, respectively).Conclusions: Substitutions conferring resistance to NS5A RCIs pre-existed in treatment-naive patients infected with HCV GT3. The effectiveness of these NS5A RCIs to exert efficacy in the clinic may depend on which inhibitor is used in combination with other antivirals. (c) 2013 Elsevier B.V. All rights reserved.