Effect of Oseltamivir Carboxylate Consumption on Emergence of Drug-Resistant H5N2 Avian Influenza Virus in Mallard Ducks
Effect of Oseltamivir Carboxylate Consumption on Emergence of Drug-Resistant H5N2 Avian Influenza Virus in Mallard Ducks
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DOI：
10.1128/aac.02126-12
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发表时间：
2013-05-01
影响因子：
4.9
通讯作者：
Bowen, Richard A.
中科院分区：
文献类型：
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作者：
Achenbach, Jenna E.;Bowen, Richard A.
最近人类流感季节期间，在环境水中检测到了不同浓度的羧酸奥司他韦（OC），反映了该药物的使用水平和稳定性。考虑到水禽作为可能导致人类感染的流感病毒宿主的作用，我们评估了摄入低剂量OC对感染两种不同低致病性(LP) H5N2禽流感病毒(AIV)的绿头鸭(Anas platyrhynchos)产生奥司他韦耐药流感病毒突变体的影响。我们在感染 A/Mallard/Minnesota/182742/1998 (H5N2) 并暴露于 1,000 ng/升 OC 的 6 只野鸭中，有 4 只检测到携带已知奥司他韦抗性分子标记（神经氨酸酶 E119V）的病毒变体的发展。该突变在第 5 至 6 天首次以少数群体形式出现，并在第 6 至 8 天成为显性基因型。在未接触该药物的鸭子或感染第二种病毒株并类似接触 OC 的鸭子的病毒中未检测到奥司他韦耐药突变。携带E119V突变的病毒分离株在体外表现出与野生型病毒相似的复制动力学，但在体内，在没有OC的情况下，E119V病毒迅速恢复为野生型，并且只有野生型亲本毒株被传播给接触鸭。这些结果表明，野生水禽在饮用水中摄入 OC 可能会促进某些 H5N2 AIV 菌株中 E119V 抗性突变的选择，从而导致病毒感染人类。
Oseltamivir carboxylate (OC) has been detected in environmental waters at various levels during recent influenza seasons in humans, reflecting levels of usage and stability of this drug. In consideration of the role of waterfowl as hosts for influenza viruses that may contribute to human infections, we evaluated the effect of consumption of low doses of OC on development of oseltamivir-resistant influenza virus mutants in mallard ducks (Anas platyrhynchos) infected with two different low-pathogenic (LP) H5N2 avian influenza viruses (AIV). We detected development of virus variants carrying a known molecular marker of oseltamivir resistance (neuraminidase E119V) in 4 out of 6 mallards infected with A/Mallard/Minnesota/182742/1998 (H5N2) and exposed to 1,000 ng/liter OC. The mutation first appeared as a minor population on days 5 to 6 and was the dominant genotype on days 6 to 8. Oseltamivir-resistant mutations were not detected in virus from ducks not exposed to the drug or in ducks infected with a second strain of virus and similarly exposed to OC. Virus isolates carrying the E119V mutation displayed in vitro replication kinetics similar to those of the wild-type virus, but in vivo, the E119V virus rapidly reverted back to wild type in the absence of OC, and only the wild-type parental strain was transmitted to contact ducks. These results indicate that consumption by wild waterfowl of OC in drinking water may promote selection of the E119V resistance mutation in some strains of H5N2 AIV that could contribute to viruses infecting human populations.