Oseltamivir-Resistant Influenza A (H1N1) Virus Strain with an H274Y Mutation in Neuraminidase Persists without Drug Pressure in Infected Mallards
Oseltamivir-Resistant Influenza A (H1N1) Virus Strain with an H274Y Mutation in Neuraminidase Persists without Drug Pressure in Infected Mallards
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DOI：
10.1128/aem.04034-14
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发表时间：
2015-04-01
影响因子：
4.4
通讯作者：
Jarhult, Josef D.
中科院分区：
文献类型：
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作者：
Gillman, Anna;Muradrasoli, Shaman;Jarhult, Josef D.
甲型流感病毒（IAV）在野生水禽中有其天然宿主，而新出现的人类IAV通常含有来自禽类病毒的基因片段。奥司他韦的活性药物代谢物（奥司他韦羧酸盐[OC]），作为达菲储存，用于流感大流行的预防，不能通过传统的污水处理去除，并已在河水中检测到。在那里，它可能对水禽中的禽IAV施加进化压力，导致抗性病毒变体的发展。只有当耐药性不限制病毒适应性，并且耐药性病毒可以在没有持续药物压力的情况下持续存在时，耐药性禽流感病毒才能在野鸟中传播。在这项绿头鸭（Anas platyrhynchos）体内研究中，我们测试了在神经氨酸酶（NA-H274 Y）中具有H274 Y突变的OC耐药性禽IAV（H1N1）毒株是否可以在逐渐消除药物压力的同时保持耐药性。成功感染野鸭暴露于降低水平的OC，粪便样本进行了分析的神经氨酸酶序列和表型抗性。在实验过程中没有观察到野生型病毒的逆转，其中包括10只暴露于低于抗性诱导水平的OC浓度的鸭子之间17天的病毒传播。我们的结论是，在禽IAV的天然宿主暴露于OC诱导的耐药性可以持续在没有药物。因此，从野鸟中传播的IAV进化而来的人类致病性IAV可能含有抗性突变的风险。对奥司他韦具有耐药性的大流行性IAV将对公共卫生构成重大威胁。因此，我们的观察强调了谨慎使用奥司他韦、升级污水处理和监测野鸟中耐药性IAV的必要性。
Influenza A virus (IAV) has its natural reservoir in wild waterfowl, and emerging human IAVs often contain gene segments from avian viruses. The active drug metabolite of oseltamivir (oseltamivir carboxylate [OC]), stockpiled as Tamiflu for influenza pandemic preparedness, is not removed by conventional sewage treatment and has been detected in river water. There, it may exert evolutionary pressure on avian IAV in waterfowl, resulting in the development of resistant viral variants. A resistant avian IAV can circulate among wild birds only if resistance does not restrict viral fitness and if the resistant virus can persist without continuous drug pressure. In this in vivo mallard (Anas platyrhynchos) study, we tested whether an OC-resistant avian IAV (H1N1) strain with an H274Y mutation in the neuraminidase (NA-H274Y) could retain resistance while drug pressure was gradually removed. Successively infected mallards were exposed to decreasing levels of OC, and fecal samples were analyzed for the neuraminidase sequence and phenotypic resistance. No reversion to wild-type virus was observed during the experiment, which included 17 days of viral transmission among 10 ducks exposed to OC concentrations below resistance induction levels. We conclude that resistance in avian IAV that is induced by exposure of the natural host to OC can persist in the absence of the drug. Thus, there is a risk that human-pathogenic IAVs that evolve from IAVs circulating among wild birds may contain resistance mutations. An oseltamivir-resistant pandemic IAV would pose a substantial public health threat. Therefore, our observations underscore the need for prudent oseltamivir use, upgraded sewage treatment, and surveillance for resistant IAVs in wild birds.