Functional neuraminidase inhibitor resistance motifs in avian influenza A(H5Nx) viruses.
Functional neuraminidase inhibitor resistance motifs in avian influenza A(H5Nx) viruses.
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DOI：
10.1016/j.antiviral.2020.104886
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发表时间：
2020-10
影响因子：
7.6
通讯作者：
Shelton H
中科院分区：
文献类型：
--
作者：
Bialy D;Shelton H
神经氨酸酶抑制剂（NAIs）是全球推荐用于治疗或预防人类流感病毒感染的抗病毒药。过去由禽流感病毒（AIV）引起的人畜共患感染所引发的流感病毒大流行以及越来越多的人感染AIV的情况表明，了解可能跨越物种障碍的禽流感病毒对NAI的耐药性非常重要。在这项研究中，我们将先前在人类感染中发现的四种NAI耐药相关突变（N2编号）引入到威胁家禽业和人类健康的H5 Nx基因型的三种当前AIV亚型的NA中：高致病性H5 N8，H5 N6和H5 N2。使用已建立的MUNANA检测，我们发现H5 N6和H5 N2病毒中的R292 K取代显著降低了对三种已获得许可的NAI的敏感性：奥司他韦、扎那米韦和帕拉米韦。相比之下，突变E119 V，H274 Y和N294 S具有更多可变的影响，NAI敏感性是药物和菌株特异性的。我们测量了耐NAI的H5 N6病毒的复制适应性，发现它们在原代鸡细胞和含胚鸡蛋中的复制滴度与野生型相比相当或显著更高-尽管病毒神经氨酸酶蛋白的NA活性降低。R292 K和N294 S耐药H5 N6病毒在其血凝素（HA）中分别具有单个氨基酸取代：Y 98 F和A189 T（H3编号），这降低了受体结合特性，可能平衡了所观察到的NA活性降低。我们的研究结果表明，H5 Nx病毒可以支持耐药突变，赋予降低易感性的许可NAIs和这些H5 N6病毒没有表现出减少在禽类细胞培养的复制适应性。我们的研究结果支持持续监测鸟类种群中这些菌株的要求，包括与人类耐药性相关的图案。NA中R292 K残基的变化降低了H5 N6和H5 N2禽流感病毒对NA抑制剂药物（NAI）的敏感性。所有四种突变（E119 V、H274 Y、R292 K和N294 S）降低了H5 N6病毒对NAI的敏感性，降低了病毒NA活性。H5 N6对NA抑制剂敏感性的降低并没有减弱病毒在鸡细胞或鸡蛋中的复制效率。在NA活性降低的H5 N6病毒中观察到病毒HA对唾液酸的亲和力降低。
Neuraminidase inhibitors (NAIs) are antiviral agents recommended worldwide to treat or prevent influenza virus infections in humans. Past influenza virus pandemics seeded by zoonotic infection by avian influenza viruses (AIV) as well as the increasing number of human infections with AIV have shown the importance of having information about resistance to NAIs by avian NAs that could cross the species barrier. In this study we introduced four NAI resistance-associated mutations (N2 numbering) previously found in human infections into the NA of three current AIV subtypes of the H5Nx genotype that threaten the poultry industry and human health: highly pathogenic H5N8, H5N6 and H5N2. Using the established MUNANA assay we showed that a R292K substitution in H5N6 and H5N2 viruses significantly reduced susceptibility to three licenced NAIs: oseltamivir, zanamivir and peramivir. In contrast the mutations E119V, H274Y and N294S had more variable effects with NAI susceptibility being drug- and strain-specific. We measured the replicative fitness of NAI resistant H5N6 viruses and found that they replicated to comparable or significantly higher titres in primary chicken cells and in embryonated hens’ eggs as compared to wild type - despite the NA activity of the viral neuraminidase proteins being reduced. The R292K and N294S drug resistant H5N6 viruses had single amino acid substitutions in their haemagglutinin (HA): Y98F and A189T, respectively (H3 numbering) which reduced receptor binding properties possibly balancing the reduced NA activity seen. Our results demonstrate that the H5Nx viruses can support drug resistance mutations that confer reduced susceptibility to licenced NAIs and that these H5N6 viruses did not show diminished replicative fitness in avian cell cultures. Our results support the requirement for on-going surveillance of these strains in bird populations to include motifs associated with human drug resistance. A R292K residue change in NA reduces susceptibility to NA inhibitor drugs (NAIs) in H5N6 and H5N2 avian influenza viruses. All four mutations (E119V, H274Y, R292K and N294S) reducing susceptibility to NAIs in H5N6 viruses reduced viral NA activity. Reduced susceptibility to NA inhibitors in H5N6 did not attenuate virus replication efficiency in chicken cells or eggs. A reduction of the viral HA affinity for sialic acid was observed in H5N6 viruses with reduced NA activity.
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