Oseltamivir-resistant pandemic A/H1N1 virus is as virulent as its wild-type counterpart in mice and ferrets.
Oseltamivir-resistant pandemic A/H1N1 virus is as virulent as its wild-type counterpart in mice and ferrets.
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DOI：
10.1371/journal.ppat.1001015
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发表时间：
2010-07-22
期刊：
影响因子：
6.7
通讯作者：
Boivin G
中科院分区：
文献类型：
--
作者：
Hamelin ME;Baz M;Abed Y;Couture C;Joubert P;Beaulieu E;Bellerose N;Plante M;Mallett C;Schumer G;Kobinger GP;Boivin G
神经氨酸酶抑制剂奥司他韦目前用于治疗感染大流行性甲型H1N1（pH 1 N1）流感病毒的患者，尽管耐药突变体可能迅速出现并可能传播。我们描述了一对奥司他韦耐药和奥司他韦敏感的pH 1 N1临床分离株的特征，其不同之处在于神经氨酸酶蛋白的单一变化（H274 Y）。通过测定MDCK α 2，6细胞中的复制动力学在体外评估pH 1 N1分离株的病毒适应度，并通过对BALB/c小鼠和雪貂进行实验性感染在体内评估病毒适应度。尽管在前24小时内突变体分离株的体外繁殖略有减少，但野生型（WT）和突变体耐药病毒在小鼠和雪貂中诱导了相似的最大体重减轻，在雪貂中具有相同的发热反应（AUC为233.9和233.2，P = 0.5156）。 类似地，WT和突变株在感染后第1、3、6和9天在小鼠肺中以及在第1-7天在雪貂鼻洗液中获得了相当的滴度。在感染H274 Y突变体的小鼠的肺中注意到更重要的血管周围（第6天）和胸膜（第6天和第12天）炎症，这与IL-6和KC的肺水平增加相关。在感染突变株的雪貂的淋巴结中也观察到IL-6水平的增加。此外，H274 Y突变株被传递给雪貂。总之，H274 Y pH 1 N1分离株的病毒适应性没有实质性改变，并有可能诱导严重疾病和传播。在2009年新型甲型H1N1（pH 1 N1）病毒大流行期间，世界卫生组织建议将奥司他韦作为一线药物，用于治疗导致住院的严重感染患者和患有易患肺部并发症的基础疾病的患者。奥司他韦耐药分离株于2009年6月底开始出现，目前全世界报告了100多个菌株，包括可能发生耐药病毒传播的少数疫情。我们的特点是健身的一对奥司他韦敏感和奥司他韦耐药菌株出现在同一家族簇，不同的神经氨酸酶蛋白只有一个单一的变化（H274 Y）。我们发现，在小鼠和雪貂中，耐药（突变）病毒的毒性至少与药物敏感（野生型）病毒一样。基于这些数据，我们认为H274 Y pH 1 N1突变株有可能在人群中传播，并最终取代敏感株，这一现象已经在季节性A/布里斯班/59/2007型（H1 N1）病毒中观察到。
The neuraminidase inhibitor oseltamivir is currently used for treatment of patients infected with the pandemic A/H1N1 (pH1N1) influenza virus, although drug-resistant mutants can emerge rapidly and possibly be transmitted. We describe the characteristics of a pair of oseltamivir-resistant and oseltamivir-susceptible pH1N1 clinical isolates that differed by a single change (H274Y) in the neuraminidase protein. Viral fitness of pH1N1 isolates was assessed in vitro by determining replication kinetics in MDCK α2,6 cells and in vivo by performing experimental infections of BALB/c mice and ferrets. Despite slightly reduced propagation of the mutant isolate in vitro during the first 24 h, the wild-type (WT) and mutant resistant viruses induced similar maximum weight loss in mice and ferrets with an identical pyrexic response in ferrets (AUC of 233.9 and 233.2, P = 0.5156). Similarly, comparable titers were obtained for the WT and the mutant strains on days 1, 3, 6 and 9 post-infection in mouse lungs and on days 1–7 in ferret nasal washes. A more important perivascular (day 6) and pleural (days 6 and 12) inflammation was noted in the lungs of mice infected with the H274Y mutant, which correlated with increased pulmonary levels of IL-6 and KC. Such increased levels of IL-6 were also observed in lymph nodes of ferrets infected with the mutant strain. Furthermore, the H274Y mutant strain was transmitted to ferrets. In conclusion, viral fitness of the H274Y pH1N1 isolate is not substantially altered and has the potential to induce severe disease and to disseminate. During the 2009 pandemic of the novel A/H1N1 (pH1N1) virus, the World Health Organization recommended oseltamivir as first-line agent for treatment of patients with severe infections leading to hospitalization and for those with underlying diseases predisposing to pulmonary complications. Oseltamivir-resistant isolates started to emerge at the end of June 2009 with now more than 100 strains reported worldwide including a few outbreaks where transmission of resistant viruses may have occurred. We characterized the fitness of a pair of oseltamivir-susceptible and oseltamivir-resistant strains emerging from the same familial cluster and that differed by only a single change (H274Y) in the neuraminidase protein. We found that the drug-resistant (mutant) virus was at least as virulent as the drug-susceptible (wild-type) virus in mice and ferrets. Based on these data, we believe that the H274Y pH1N1 mutant strain has the potential to disseminate in the population and to eventually replace the susceptible strain, a phenomenon that has been already observed with seasonal A/Brisbane/59/2007-like (H1N1) viruses.
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