Generation and characterization of influenza A viruses with altered polymerase fidelity.
Generation and characterization of influenza A viruses with altered polymerase fidelity.
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DOI：
10.1038/ncomms5794
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发表时间：
2014-09-03
影响因子：
16.6
通讯作者：
Yen, Hui-Ling
中科院分区：
文献类型：
--
作者：
Cheung, Peter P. H.;Watson, Simon J.;Choy, Ka-Tim;Sia, Sin Fun;Wong, Diana D. Y.;Poon, Leo L. M.;Kellam, Paul;Guan, Yi;Peiris, J. S. Malik;Yen, Hui-Ling
通过容易出错的RNA依赖性RNA聚合酶（RdRP）或基因重排获得的甲型流感病毒（IAV）的遗传多样性使IAV能够通过流行病或大流行在人类中持续存在。在这里，为了评估通过RdRP获得的遗传多样性的生物学意义，我们表征了IAV保真度变体，其来源于在利巴韦林存在下传代季节性H3 N2病毒，所述利巴韦林是一种嘌呤类似物，其增加鸟苷至腺苷突变。我们证明了单个PB 1-V43 I突变增加了A/武汉/359/95（H3 N2）和A/越南/1203/04（H5 N1）病毒对鸟苷的选择性。H5 N1 PB 1-V43 I重组病毒在体外或小鼠肺中复制到与野生型病毒相当的滴度。然而，接种后第3天病毒群体多样性的降低与小鼠中致死率和嗜神经性降低10倍相关。应用一个保真度变异与减少突变频率，我们提供了直接的实验证据的遗传多样性在IAV发病机制中的作用。
Genetic diversity of influenza A viruses (IAV) acquired through the error-prone RNA-dependent RNA polymerase (RdRP) or genetic reassortment enables perpetuation of IAV in humans through epidemics or pandemics. Here, to assess the biological significance of genetic diversity acquired through RdRP, we characterize an IAV fidelity variant derived from passaging a seasonal H3N2 virus in the presence of ribavirin, a purine analog that increases guanosine-to-adenosine mutations. We demonstrate that a single PB1-V43I mutation increases selectivity to guanosine in A/Wuhan/359/95 (H3N2) and A/Vietnam/1203/04 (H5N1) viruses. The H5N1 PB1-V43I recombinant virus replicates to comparable titres as the wild-type virus in vitro or in the mouse lungs. However, a decrease in viral population diversity at day 3 post-inoculation is associated with a 10-fold reduced lethality and neurotropism in mice. Applying a fidelity variant with reduced mutational frequency, we provide direct experimental evidence for the role of genetic diversity in IAV pathogenesis.
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影响因子：
6.7
作者：
Pfeiffer JK;Kirkegaard K
通讯作者：
Kirkegaard K
DOI：
10.1073/pnas.1111650108
发表时间：
2011-09-20
影响因子：
11.1
作者：
Coffey, Lark L.;Beeharry, Yasnee;Vignuzzi, Marco
通讯作者：
Vignuzzi, Marco
影响因子：
7.6
作者：
WRAY, SK;GILBERT, BE;KNIGHT, V
通讯作者：
KNIGHT, V
影响因子：
6.7
作者：
Levi LI;Gnädig NF;Beaucourt S;McPherson MJ;Baron B;Arnold JJ;Vignuzzi M
通讯作者：
Vignuzzi M
DOI：
10.1073/pnas.1232294100
发表时间：
2003-06-10
影响因子：
11.1
作者：
Pfeiffer, JK;Kirkegaard, K
通讯作者：
Kirkegaard, K