Estimating the fitness advantage conferred by permissive neuraminidase mutations in recent oseltamivir-resistant A(H1N1)pdm09 influenza viruses.
Estimating the fitness advantage conferred by permissive neuraminidase mutations in recent oseltamivir-resistant A(H1N1)pdm09 influenza viruses.
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DOI：
10.1371/journal.ppat.1004065
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发表时间：
2014-04
期刊：
影响因子：
6.7
通讯作者：
Hurt AC
中科院分区：
文献类型：
--
作者：
Butler J;Hooper KA;Petrie S;Lee R;Maurer-Stroh S;Reh L;Guarnaccia T;Baas C;Xue L;Vitesnik S;Leang SK;McVernon J;Kelso A;Barr IG;McCaw JM;Bloom JD;Hurt AC
奥司他韦是全世界依赖的治疗人类流感感染的首选药物。对奥司他韦耐药性进行常规监测，以确保奥司他韦对循环病毒持续有效。自2009年甲型H1N1流感病毒（A（H1N1）pdm 09）大流行出现以来，对奥司他韦耐药（OR）的A（H1N1）pdm 09病毒的比例一般较低。然而，2011年在澳大利亚未接受奥司他韦治疗的社区患者中检测到一组编码神经氨酸酶（NA）H275 Y奥司他韦耐药突变的ORA（H1N1）pdm 09病毒。在这里，我们结合联合收割机的竞争混合物雪貂模型的流感感染的数学模型，以评估健身，无论是在主机内和之间，最近OR A（H1N1）pdm 09病毒。结合NA表达和活性的体外分析数据，我们证明当代A（H1N1）pdm 09病毒现在比2009年传播的早期A（H1N1）pdm 09病毒更能够获得H275 Y而不损害其适应性。此外，使用反向工程病毒，我们证明了一对允许的二级NA突变，V241 I和N369 K，赋予最近的H275 Y A（H1N1）pdm 09病毒强大的适应性，这与增强的表面表达和A（H1N1）pdm 09 NA蛋白的酶活性相关。这些允许突变首次出现在2010年，现在几乎存在于所有流行的A（H1N1）pdm 09病毒中。我们的研究结果表明，最近的A（H1N1）pdm 09病毒现在比早期的A（H1N1）pdm 09病毒更容易获得H275 Y，增加了OR A（H1N1）pdm 09出现并在全球传播的风险。抗菌素耐药性是治疗感染性疾病的一个日益严重的问题。2007-2008年，人类季节性甲型H1N1流感病毒通过神经氨酸酶（NA）蛋白中的H275 Y氨基酸突变，迅速获得了对最常用的抗流感药物奥司他韦的耐药性。2009年，对奥司他韦敏感的甲型（H1N1）pdm 09病毒（编码NA 275 H）在人群中出现，迅速取代了对奥司他韦耐药的季节性甲型（H1N1）病毒。然而，人们越来越担心，目前流行的A（H1N1）pdm 09病毒可能类似地获得奥司他韦耐药性（通过NA H275 Y突变）并变得广泛传播。在这里，我们证明了两个新的氨基酸变化，目前在几乎所有最近的A（H1N1）pdm 09病毒（NA V241 I和N369 K），使收购的NA H275 Y奥司他韦耐药突变，而不损害病毒的适应性。因此，最近的A（H1N1）pdm 09病毒现在更接近获得广泛的奥司他韦耐药性。
Oseltamivir is relied upon worldwide as the drug of choice for the treatment of human influenza infection. Surveillance for oseltamivir resistance is routinely performed to ensure the ongoing efficacy of oseltamivir against circulating viruses. Since the emergence of the pandemic 2009 A(H1N1) influenza virus (A(H1N1)pdm09), the proportion of A(H1N1)pdm09 viruses that are oseltamivir resistant (OR) has generally been low. However, a cluster of OR A(H1N1)pdm09 viruses, encoding the neuraminidase (NA) H275Y oseltamivir resistance mutation, was detected in Australia in 2011 amongst community patients that had not been treated with oseltamivir. Here we combine a competitive mixtures ferret model of influenza infection with a mathematical model to assess the fitness, both within and between hosts, of recent OR A(H1N1)pdm09 viruses. In conjunction with data from in vitro analyses of NA expression and activity we demonstrate that contemporary A(H1N1)pdm09 viruses are now more capable of acquiring H275Y without compromising their fitness, than earlier A(H1N1)pdm09 viruses circulating in 2009. Furthermore, using reverse engineered viruses we demonstrate that a pair of permissive secondary NA mutations, V241I and N369K, confers robust fitness on recent H275Y A(H1N1)pdm09 viruses, which correlated with enhanced surface expression and enzymatic activity of the A(H1N1)pdm09 NA protein. These permissive mutations first emerged in 2010 and are now present in almost all circulating A(H1N1)pdm09 viruses. Our findings suggest that recent A(H1N1)pdm09 viruses are now more permissive to the acquisition of H275Y than earlier A(H1N1)pdm09 viruses, increasing the risk that OR A(H1N1)pdm09 will emerge and spread worldwide. Antimicrobial resistance is an increasing problem for the treatment of infectious diseases. In 2007–2008 human seasonal A(H1N1) influenza viruses rapidly acquired resistance to the most commonly used anti-influenza drug oseltamivir, via a H275Y amino acid mutation within the neuraminidase (NA) protein. In 2009 the oseltamivir sensitive A(H1N1)pdm09 virus (encoding NA 275H) emerged in the human population, rapidly replacing the oseltamivir resistant seasonal A(H1N1) virus. However, there is increasing concern that currently circulating A(H1N1)pdm09 viruses may similarly acquire oseltamivir resistance (via the NA H275Y mutation) and become widespread. Here we demonstrate that two novel amino acid changes present in virtually all recent A(H1N1)pdm09 viruses (NA V241I and N369K) enable the acquisition of the NA H275Y oseltamivir resistance mutation without compromising viral fitness. As such recent A(H1N1)pdm09 viruses are now one step closer to acquiring widespread oseltamivir resistance.
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影响因子：
6.7
作者：
Hamelin ME;Baz M;Abed Y;Couture C;Joubert P;Beaulieu E;Bellerose N;Plante M;Mallett C;Schumer G;Kobinger GP;Boivin G
通讯作者：
Boivin G
影响因子：
5
作者：
Hurt, AC;Barr, IG;Hampson, AW
通讯作者：
Hampson, AW
影响因子：
6.7
作者：
Duan, Susu;Boltz, David A.;Govorkova, Elena A.
通讯作者：
Govorkova, Elena A.
影响因子：
5.4
作者：
Abed, Yacine;Pizzorno, Andres;Boivin, Guy
通讯作者：
Boivin, Guy
影响因子：
5.4
作者：
Bouvier, Nicole M.;Rahmat, Saad;Pica, Natalie
通讯作者：
Pica, Natalie