251. A PB1 T296R substitution enhance polymerase activity and confer a virulent phenotype to a 2009 pandemic H1N1 influenza virus in mice
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Qianyi Zhang, Yuanguo Li, Hualan Chen, Songtao Yang, Hualei Wang, Jing Huang, Tiecheng Wang, Peter R. Wilker, Yue Xin, Weiyang Sun, Zhijun Yu, Xinghai Zhang, Kun Zhang, Kaihui Cheng, Donghui Yue, Chuan Qin, Xianzhu Xia, Li Xue, and Yuwei Gao
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viruses ,Population ,Mutation, Missense ,Virulence ,Biology ,medicine.disease_cause ,H5N1 genetic structure ,Virus ,Microbiology ,Mouse model ,Mice ,Viral Proteins ,Influenza A Virus, H1N1 Subtype ,Serial passage ,Virology ,Influenza, Human ,Influenza A virus ,medicine ,Animals ,Humans ,education ,education.field_of_study ,Mice, Inbred BALB C ,H1N1 ,virus diseases ,Reverse genetics ,Viral replication ,Amino Acid Substitution ,Female - Abstract
While the 2009 pandemic H1N1 virus has become established in the human population as a seasonal influenza virus, continued adaptation may alter viral virulence. Here, we passaged a 2009 pandemic H1N1 virus (A/Changchun/01/2009) in mice. Serial passage in mice generated viral variants with increased virulence. Adapted variants displayed enhanced replication kinetics in vitro and vivo. Analysis of the variants genomes revealed 6 amino acid changes in the PB1 (T296R), PA (I94V), HA (H3 numbering; N159D, D225G, and R226Q), and NP (D375N). Using reverse genetics, we found that a PB1-T296R substitution found in all adapted viral variants enhanced viral replication kinetics in vitro and vivo, increased viral polymerase activity in human cells, and was sufficient for enhanced virulence of the 2009 pandemic H1N1 virus in mice. Therefore, we defined a novel influenza pathogenic determinant, providing further insights into the pathogenesis of influenza viruses in mammals.
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