Department of Microbiology, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029-6574, USA.
J Virol. 2010 Nov;84(21):11219-26. doi: 10.1128/JVI.01424-10. Epub 2010 Aug 25.
Oseltamivir is routinely used worldwide for the treatment of severe influenza A virus infection, and should drug-resistant pandemic 2009 H1N1 viruses become widespread, this potent defense strategy might fail. Oseltamivir-resistant variants of the pandemic 2009 H1N1 influenza A virus have been detected in a substantial number of patients, but to date, the mutant viruses have not moved into circulation in the general population. It is not known whether the resistance mutations in viral neuraminidase (NA) reduce viral fitness. We addressed this question by studying transmission of oseltamivir-resistant mutants derived from two different isolates of the pandemic H1N1 virus in both the guinea pig and ferret transmission models. In vitro, the virus readily acquired a single histidine-to-tyrosine mutation at position 275 (H275Y) in viral neuraminidase when serially passaged in cell culture with increasing concentrations of oseltamivir. This mutation conferred a high degree of resistance to oseltamivir but not zanamivir. Unexpectedly, in guinea pigs and ferrets, the fitness of viruses with the H275Y point mutation was not detectably impaired, and both wild-type and mutant viruses were transmitted equally well from animals that were initially inoculated with 1:1 virus mixtures to naïve contacts. In contrast, a reassortant virus containing an oseltamivir-resistant seasonal NA in the pandemic H1N1 background showed decreased transmission efficiency and fitness in the guinea pig model. Our data suggest that the currently circulating pandemic 2009 H1N1 virus has a high potential to acquire drug resistance without losing fitness.
奥司他韦在全球范围内被常规用于治疗严重的甲型流感病毒感染，如果耐药性大流行的 2009 年 H1N1 病毒广泛传播，这种有效的防御策略可能会失败。在大量患者中已经检测到大流行的 2009 年 H1N1 甲型流感病毒对奥司他韦耐药的变异株，但迄今为止，这些突变病毒尚未在普通人群中传播。目前尚不清楚病毒神经氨酸酶（NA）中的耐药突变是否会降低病毒的适应性。我们通过在豚鼠和雪貂传播模型中研究源自大流行 H1N1 病毒的两个不同分离株的奥司他韦耐药突变体的传播来解决这个问题。在体外，当病毒在含有递增浓度奥司他韦的细胞培养物中连续传代时，病毒的神经氨酸酶中很容易获得单个组氨酸到酪氨酸的突变（H275Y）。该突变赋予了对奥司他韦的高度耐药性，但对扎那米韦没有耐药性。出乎意料的是，在豚鼠和雪貂中，具有 H275Y 点突变的病毒的适应性并未明显受损，并且最初用 1:1 病毒混合物接种的动物向未感染的接触者传播时，野生型和突变型病毒的传播效率相同。相比之下，在大流行 H1N1 背景下含有奥司他韦耐药季节性 NA 的重组病毒在豚鼠模型中的传播效率和适应性降低。我们的数据表明，目前流行的 2009 年 H1N1 病毒具有很高的获得耐药性而不丧失适应性的潜力。
