Oseltamivir-Resistant Pandemic H1N1/2009 Influenza Virus Possesses Lower Transmissibility and Fitness in Ferrets
Oseltamivir-Resistant Pandemic H1N1/2009 Influenza Virus Possesses Lower Transmissibility and Fitness in Ferrets
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DOI：
10.1371/journal.ppat.1001022
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发表时间：
2010-07-01
期刊：
影响因子：
6.7
通讯作者：
Govorkova, Elena A.
中科院分区：
文献类型：
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作者：
Duan, Susu;Boltz, David A.;Govorkova, Elena A.
神经氨酸酶 (NA) 抑制剂奥司他韦为控制流感提供了一种重要的直接选择，在最近的 H1N1 大流行期间，其临床应用大幅增加。鉴于2007-2008年奥司他韦耐药季节性H1N1流感病毒的高流行，尽管分离出耐药变种的比例较低，但迫切需要表征奥司他韦耐药H1N1/2009病毒的传播性和适应性。在这里，我们在雪貂模型中研究了一对密切匹配的大流行 H1N1/2009 临床分离株（一种对奥司他韦敏感，另一种对奥司他韦耐药）的传播性。耐药 H275Y 突变体源自接受奥司他韦预防的患者，是大流行病毒中第一个对奥司他韦耐药的分离株。全基因组测序显示，这对病毒仅在 NA 氨基酸位置 275 处有所不同。我们发现，对奥司他韦耐药的 H1N1/2009 病毒不能通过呼吸道飞沫在雪貂中有效传播 (0/2)，但它保留了通过直接接触的有效传播 (2/2)。敏感的 H1N1/2009 病毒通过两种途径有效传播（分别为 2/2 和 1/2）。野生型 H1N1/2009 和耐药突变体似乎在雪貂中引起类似的病程，但临床症状没有明显减弱。我们通过将奥司他韦敏感和耐药的 H1N1/2009 病毒共同感染雪貂来比较宿主内的病毒适应性，发现耐药病毒表现出较低的生长能力（适应性）。抗性病毒的 NA 在体外表现出底物结合亲和力和催化活性降低，并延迟 MDCK 和 MDCK-SIAT1 细胞的初始生长。这些发现可能部分解释了其传播效率较低的原因。耐奥司他韦的 H1N1/2009 病毒通过直接接触保留了有效传播，这一事实强调了在大流行期间持续监测耐药性和可能进化的病毒蛋白特征的必要性。
The neuraminidase (NA) inhibitor oseltamivir offers an important immediate option for the control of influenza, and its clinical use has increased substantially during the recent H1N1 pandemic. In view of the high prevalence of oseltamivir-resistant seasonal H1N1 influenza viruses in 2007-2008, there is an urgent need to characterize the transmissibility and fitness of oseltamivir-resistant H1N1/2009 viruses, although resistant variants have been isolated at a low rate. Here we studied the transmissibility of a closely matched pair of pandemic H1N1/2009 clinical isolates, one oseltamivir-sensitive and one resistant, in the ferret model. The resistant H275Y mutant was derived from a patient on oseltamivir prophylaxis and was the first oseltamivir-resistant isolate of the pandemic virus. Full genome sequencing revealed that the pair of viruses differed only at NA amino acid position 275. We found that the oseltamivir-resistant H1N1/2009 virus was not transmitted efficiently in ferrets via respiratory droplets (0/2), while it retained efficient transmission via direct contact (2/2). The sensitive H1N1/2009 virus was efficiently transmitted via both routes (2/2 and 1/2, respectively). The wild-type H1N1/2009 and the resistant mutant appeared to cause a similar disease course in ferrets without apparent attenuation of clinical signs. We compared viral fitness within the host by co-infecting a ferret with oseltamivir-sensitive and -resistant H1N1/2009 viruses and found that the resistant virus showed less growth capability (fitness). The NA of the resistant virus showed reduced substrate-binding affinity and catalytic activity in vitro and delayed initial growth in MDCK and MDCK-SIAT1 cells. These findings may in part explain its less efficient transmission. The fact that the oseltamivir-resistant H1N1/2009 virus retained efficient transmission through direct contact underlines the necessity of continuous monitoring of drug resistance and characterization of possible evolving viral proteins during the pandemic.