Genetic compatibility and virulence of reassortants derived from contemporary avian H5N1 and human H3N2 influenza a viruses
Genetic compatibility and virulence of reassortants derived from contemporary avian H5N1 and human H3N2 influenza a viruses
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DOI：
10.1371/journal.ppat.1000072
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发表时间：
2008-05-01
期刊：
影响因子：
6.7
通讯作者：
Donis, Ruben O.
中科院分区：
文献类型：
--
作者：
Chen, Li-Mei;Davis, C. Todd;Donis, Ruben O.
流感病毒基因组的分段结构在其适应新宿主和大流行的出现中起着关键作用。尽管人们对高致病性H5N1禽流感病毒造成的大流行威胁感到担忧，但人们对H5N1病毒与当代人类流感病毒重组后可能出现的生物学特性知之甚少。在这项研究中，我们利用反向遗传学方法从H5N1和H3N2病毒中获得63种可能的病毒重组体，其中含有H5N1表面蛋白基因，并分析了它们的生存能力、复制效率和小鼠毒力。禽-人病毒基因的特定星座被证明对细胞培养中的病毒复制有害，可能是由于分子相互作用网络的破坏。特别是，异种聚合酶亚基以及NP和M或NS的显著表型被注意到。然而，近一半的重组在体外高效复制，揭示了禽流感和人类病毒基因之间的高度兼容性。13个重组基因在小鼠中表现出毒性表型，并可能对哺乳动物宿主构成最大威胁。有趣的是，最具致病性的重组病毒之一含有禽类PB1，类似于1957年和1968年的大流行病毒。我们的研究结果揭示了与H5N1/H3N2重组相关的广泛表型，以及禽类PB1在大流行性流感出现中的可能作用。这些观察结果对监测项目中发现的H5N1重组病毒的风险评估具有重要意义。
The segmented structure of the influenza virus genome plays a pivotal role in its adaptation to new hosts and the emergence of pandemics. Despite concerns about the pandemic threat posed by highly pathogenic avian influenza H5N1 viruses, little is known about the biological properties of H5N1 viruses that may emerge following reassortment with contemporary human influenza viruses. In this study, we used reverse genetics to generate the 63 possible virus reassortants derived from H5N1 and H3N2 viruses, containing the H5N1 surface protein genes, and analyzed their viability, replication efficiency, and mouse virulence. Specific constellations of avian-human viral genes proved deleterious for viral replication in cell culture, possibly due to disruption of molecular interaction networks. In particular, striking phenotypes were noted with heterologous polymerase subunits, as well as NP and M, or NS. However, nearly one-half of the reassortants replicated with high efficiency in vitro, revealing a high degree of compatibility between avian and human virus genes. Thirteen reassortants displayed virulent phenotypes in mice and may pose the greatest threat for mammalian hosts. Interestingly, one of the most pathogenic reassortants contained avian PB1, resembling the 1957 and 1968 pandemic viruses. Our results reveal the broad spectrum of phenotypes associated with H5N1/H3N2 reassortment and a possible role for the avian PB1 in the emergence of pandemic influenza. These observations have important implications for risk assessment of H5N1 reassortant viruses detected in surveillance programs.