Erasmus Medical Centre, Department of Virology, Rotterdam, The Netherlands.
PLoS Pathog. 2011 Sep;7(9):e1002276. doi: 10.1371/journal.ppat.1002276. Epub 2011 Sep 29.
Only two classes of antiviral drugs, neuraminidase inhibitors and adamantanes, are approved for prophylaxis and therapy against influenza virus infections. A major concern is that influenza virus becomes resistant to these antiviral drugs and spreads in the human population. The 2009 pandemic A/H1N1 influenza virus is naturally resistant to adamantanes. Recently a novel neuraminidase I223R mutation was identified in an A/H1N1 virus showing cross-resistance to the neuraminidase inhibitors oseltamivir, zanamivir and peramivir. However, the ability of this virus to cause disease and spread in the human population is unknown. Therefore, this clinical isolate (NL/2631-R223) was compared with a well-characterized reference virus (NL/602). In vitro experiments showed that NL/2631-I223R replicated as well as NL/602 in MDCK cells. In a ferret pathogenesis model, body weight loss was similar in animals inoculated with NL/2631-R223 or NL/602. In addition, pulmonary lesions were similar at day 4 post inoculation. However, at day 7 post inoculation, NL/2631-R223 caused milder pulmonary lesions and degree of alveolitis than NL/602. This indicated that the mutant virus was less pathogenic. Both NL/2631-R223 and a recombinant virus with a single I223R change (recNL/602-I223R), transmitted among ferrets by aerosols, despite observed attenuation of recNL/602-I223R in vitro. In conclusion, the I223R mutated virus isolate has comparable replicative ability and transmissibility, but lower pathogenicity than the reference virus based on these in vivo studies. This implies that the 2009 pandemic influenza A/H1N1 virus subtype with an isoleucine to arginine change at position 223 in the neuraminidase has the potential to spread in the human population. It is important to be vigilant for this mutation in influenza surveillance and to continue efforts to increase the arsenal of antiviral drugs to combat influenza.
目前仅有两类抗病毒药物（神经氨酸酶抑制剂和金刚烷胺）被批准用于预防和治疗流感病毒感染。人们主要担心的是流感病毒会对这些抗病毒药物产生耐药性，并在人群中传播。2009 年大流行的 A/H1N1 流感病毒天然对金刚烷胺耐药。最近，在一株对神经氨酸酶抑制剂奥司他韦、扎那米韦和帕拉米韦具有交叉耐药性的 A/H1N1 病毒中发现了一种新的神经氨酸酶 I223R 突变。然而，这种病毒引起疾病并在人群中传播的能力尚不清楚。因此，对该临床分离株（NL/2631-R223）与一株特征明确的参考病毒（NL/602）进行了比较。体外实验表明，NL/2631-I223R 在 MDCK 细胞中的复制能力与 NL/602 相似。在雪貂发病模型中，接种 NL/2631-R223 或 NL/602 的动物体重减轻情况相似。此外，接种后第 4 天肺部病变也相似。然而，接种后第 7 天，NL/2631-R223 引起的肺部病变和肺泡炎程度比 NL/602 轻。这表明突变病毒的致病性较低。NL/2631-R223 和一株仅含有 I223R 单一突变的重组病毒（recNL/602-I223R）都可通过气溶胶在雪貂间传播，尽管体外观察到 recNL/602-I223R 的复制能力减弱。总之，基于这些体内研究，与参考病毒相比，I223R 突变病毒分离株具有相当的复制能力和传播能力，但致病性较低。这意味着 2009 年大流行的 A/H1N1 流感病毒亚型在神经氨酸酶的 223 位由异亮氨酸突变为精氨酸，有可能在人群中传播。在流感监测中对该突变保持警惕并继续努力增加抗病毒药物的储备以对抗流感非常重要。
