Comprehensive assessment of 2009 pandemic influenza A (H1N1) virus drug susceptibility in vitro
Comprehensive assessment of 2009 pandemic influenza A (H1N1) virus drug susceptibility in vitro
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DOI：
10.3851/imp1678
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发表时间：
2010-01-01
影响因子：
1.2
通讯作者：
Klimov, Alexander I.
中科院分区：
文献类型：
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作者：
Gubareva, Larisa V.;Trujillo, A. Angelica;Klimov, Alexander I.
背景：抗病毒药物是控制流感病毒感染的重要选择。本研究评估了2009年4月至2010年1月在全球收集的2009年甲型H1N1流感大流行病毒的药物敏感性。方法：对分离的病毒进行金刚烷敏感性检测，采用焦磷酸测序法检测M2蛋白中金刚烷抗性的S31N标记，并采用生物学方法评估病毒在细胞培养中的复制情况。为评价神经氨酸酶（NA）抑制剂（NAI）的敏感性，采用化学发光NA抑制法和焦磷酸测序法检测NA中奥司他韦耐药标志物H275Y （N2编号为H274Y）。结果：除3种病毒外，所有进行金刚烷敏感性测试的病毒（n=3,362）都对这类药物具有耐药性。所有检测NAI敏感性的病毒（n=3,359）均对美国食品和药物管理局批准的两种NAI敏感，即奥司他韦（平均+/- SD 50%抑制浓度（IC50） 0.25 +/- 0.12 nM）和扎那米韦（平均IC50 0.29 +/- 0.09 nM），除了23株（0.7%）对奥司他韦耐药，但对扎那米韦敏感。奥司他韦耐药病毒在其NA中有H275Y突变，并在通过预防或治疗接触该药物的患者中检测到。所有病毒的NA活性均被NAls peramivir、laninamivir （R-125489）和A-315675所抑制，但H275Y变体对peramivir的敏感性降低了约100倍。结论：本报告提供了2009年甲型H1N1流感监测病毒的抗病毒药物敏感性数据，其中大多数病毒对金刚烷类耐药，对NAls敏感。这些发现为监测抗病毒药物耐药性和开发用于检测流感抗病毒药物耐药性的新型诊断试验提供了必要的信息。
Background: Antiviral drugs are an important option for managing infections caused by influenza viruses. This study assessed the drug susceptibility of 2009 pandemic influenza A (H1N1) viruses collected globally between April 2009 and January 2010.Methods: Virus isolates were tested for adamantane susceptibility, using pyrosequencing to detect the S31N marker of adamantane resistance in the M2 protein and biological assays to assess viral replication in cell culture. To assess neuraminidase (NA) inhibitor (NAI) susceptibility, virus isolates were tested in chemiluminescent NA inhibition assays and by pyrosequencing to detect the H275Y (H274Y in N2 numbering) marker of oseltamivir resistance in the NA.Results: With the exception of three, all viruses that were tested for adamantane susceptibility (n=3,362) were resistant to this class of drugs. All viruses tested for NAI susceptibility (n=3,359) were sensitive to two US Food and Drug Administration-approved NAIs, oseltamivir (mean +/- SD 50% inhibitory concentration (IC50] 0.25 +/- 0.12 nM) and zanamivir (mean IC50 0.29 +/- 0.09 nM), except 23 (0.7%), which were resistant to oseltamivir, but sensitive to zanamivir. Oseltamivir-resistant viruses had the H275Y mutation in their NA and were detected in patients exposed to the drug through prophylaxis or treatment. NA activity of all viruses was inhibited by the NAls peramivir, laninamivir (R-125489) and A-315675, except for H275Y variants, which exhibited approximately 100-fold reduction in peramivir susceptibility.Conclusions: This report provides data regarding antiviral susceptibility of 2009 pandemic influenza A (H1N1) surveillance viruses, the majority of which were resistant to adamantanes and sensitive to NAls. These findings provide information essential for antiviral resistance monitoring and development of novel diagnostic tests for detecting influenza antiviral resistance.