Oseltamivir-resistant influenza viruses get by with a little help from permissive mutations.
Oseltamivir-resistant influenza viruses get by with a little help from permissive mutations.
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DOI：
10.1586/eri.11.2
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发表时间：
2011-04
影响因子：
5.7
通讯作者：
Hensley SE
中科院分区：
文献类型：
--
作者：
Myers JL;Hensley SE
甲型流感病毒（IAV）编码两种关键糖蛋白，血凝素和神经氨酸酶（NA）。血凝素通过与IAV的受体、唾液酸和NA的相互作用促进病毒对接到细胞上，通过切割细胞和病毒唾液酸促进新合成的病毒体的释放。NA抑制剂，如奥司他韦，是广泛使用的药物，通过结合NA的活性位点发挥作用。虽然在多年前的实验室实验中很容易产生对奥司他韦具有抗药性的病毒，但人们普遍认为，这些病毒不能在人群中传播，因为它们不能有效地复制。然而，奥司他韦耐药H1N1病毒在2007-2008年IAV季节迅速传播，这些病毒含有与多年前鉴定的完全相同的耐药突变，即NA残基274（H274 Y）处的组氨酸取代为酪氨酸。与实验衍生的NA耐药病毒不同，2007-2008年H1N1病毒含有H274 Y有效复制。Bloom等人通过鉴定允许病毒耐受H274 Y的允许NA突变解决了这个谜题。在这里，我们讨论了这些重要的发现，并推测这些研究如何有助于在未来早期发现耐药菌株。
Influenza A viruses (IAVs) encode two critical glycoproteins, hemagglutinin and neuraminidase (NA). Hemagglutinin promotes viral docking onto cells via interactions with IAV’s receptor, sialic acid and NA facilitates release of newly synthesized virions by cleaving cellular and viral sialic acid. NA inhibitors, such as oseltamivir, are widely used drugs that work by binding to the active site of NA. Although oseltamivir-resistant viruses were easily generated years ago in laboratory experiments, it was widely believed that these viruses would not be able to circulate in the human population as they did not replicate efficiently. However, oseltamivir-resistant H1N1 viruses rapidly spread during the 2007–2008 IAV season and these viruses contained precisely the same exact drug-resistance mutation identified years prior, a histidine to tyrosine substitution at NA residue 274 (H274Y). Unlike the experimentally derived NA inhibitor-resistant viruses, 2007–2008 H1N1 viruses containing H274Y replicated efficiently. Bloom et al. have solved this riddle by identifying permissive NA mutations that allow viruses to tolerate H274Y. Here, we discuss these important findings and speculate how these studies may facilitate early detection of drug-resistant strains in the future.
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