Gubareva Larisa V, Trujillo A Angelica, Okomo-Adhiambo Margaret, Mishin Vasiliy P, Deyde Varough M, Sleeman Katrina, Nguyen Ha T, Sheu Tiffany G, Garten Rebecca J, Shaw Michael W, Fry Alicia M, Klimov Alexander I
Virus Surveillance and Diagnosis Branch, Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Antivir Ther. 2010;15(8):1151-9. doi: 10.3851/IMP1678.
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.
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.
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 [IC(50)] 0.25 ±0.12 nM) and zanamivir (mean IC(50) 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 NAIs peramivir, laninamivir (R-125489) and A-315675, except for H275Y variants, which exhibited approximately 100-fold reduction in peramivir susceptibility.
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 NAIs. These findings provide information essential for antiviral resistance monitoring and development of novel diagnostic tests for detecting influenza antiviral resistance.
抗病毒药物是治疗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月期间全球收集的2009年甲型H1N1大流行性流感病毒的药物敏感性。
采用焦磷酸测序法检测M2蛋白中金刚烷抗性的S31N标记，并通过生物学试验评估病毒在细胞培养中的复制情况，对病毒分离株进行金刚烷敏感性检测。为评估神经氨酸酶（NA）抑制剂（NAI）的敏感性，在化学发光NA抑制试验中对病毒分离株进行检测，并通过焦磷酸测序法检测NA中对奥司他韦耐药的H275Y（N2编号中的H274Y）标记。
除3株外，所有接受金刚烷敏感性检测的病毒（n = 3362）均对这类药物耐药。所有接受NAI敏感性检测的病毒（n = 3359）对两种美国食品药品监督管理局批准的NAI敏感，即奥司他韦（平均±标准差50%抑制浓度[IC(50)] 0.25±0.12 nM）和扎那米韦（平均IC(50) 0.29±0.09 nM），但有23株（0.7%）对奥司他韦耐药，对扎那米韦敏感。对奥司他韦耐药的病毒在其NA中具有H275Y突变，在通过预防或治疗接触过该药物的患者中检测到。除H275Y变异株外，所有病毒的NA活性均被帕拉米韦、拉尼米韦（R - 125489）和A - 315675抑制，H275Y变异株对帕拉米韦的敏感性降低约100倍。
本报告提供了关于2009年甲型H1N1大流行性流感监测病毒抗病毒敏感性的数据，其中大多数对金刚烷耐药，对NAI敏感。这些发现为抗病毒耐药性监测和开发检测流感抗病毒耐药性的新型诊断试验提供了重要信息。
