Immunology Program, The Wistar Institute, Philadelphia, PA 19104, USA.
Expert Rev Anti Infect Ther. 2011 Apr;9(4):385-8. doi: 10.1586/eri.11.2.
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.
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、唾液酸的相互作用促进病毒附着在细胞上，而 NA 通过切割细胞和病毒上的唾液酸促进新合成的病毒释放。神经氨酸酶抑制剂，如奥司他韦，是广泛使用的药物，通过与 NA 的活性位点结合而起作用。尽管几年前在实验室实验中很容易产生对奥司他韦耐药的病毒，但人们普遍认为这些病毒不会在人群中传播，因为它们的复制效率不高。然而，对奥司他韦耐药的 H1N1 病毒在 2007-2008 年 IAV 季节迅速传播，这些病毒恰好含有与多年前鉴定的相同的耐药突变，即 NA 残基 274 处的组氨酸到酪氨酸取代（H274Y）。与实验衍生的 NA 抑制剂耐药病毒不同，含有 H274Y 的 2007-2008 年 H1N1 病毒能够高效复制。Bloom 等人通过鉴定允许病毒耐受 H274Y 的允许性 NA 突变解决了这个难题。在这里，我们讨论这些重要发现，并推测这些研究如何有助于未来及早发现耐药菌株。
