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PLoS Pathog. 2016 Apr 20;12(4):e1005583. doi: 10.1371/journal.ppat.1005583. eCollection 2016 Apr.

Novel Polymerase Gene Mutations for Human Adaptation in Clinical Isolates of Avian H5N1 Influenza Viruses.

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Department of Viral infection, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Department of Infectious Diseases, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Department of Microbiology, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt.
Department of Laboratory Examination, International University of Health and Welfare Hospital, Tochigi, Japan.
Health Science Hills, College of Life and Health Sciences, Chubu University, Aichi, Japan.


A major determinant in the change of the avian influenza virus host range to humans is the E627K substitution in the PB2 polymerase protein. However, the polymerase activity of avian influenza viruses with a single PB2-E627K mutation is still lower than that of seasonal human influenza viruses, implying that avian viruses require polymerase mutations in addition to PB2-627K for human adaptation. Here, we used a database search of H5N1 clade 2.2.1 virus sequences with the PB2-627K mutation to identify other polymerase adaptation mutations that have been selected in infected patients. Several of the mutations identified acted cooperatively with PB2-627K to increase viral growth in human airway epithelial cells and mouse lungs. These mutations were in multiple domains of the polymerase complex other than the PB2-627 domain, highlighting a complicated avian-to-human adaptation pathway of avian influenza viruses. Thus, H5N1 viruses could rapidly acquire multiple polymerase mutations that function cooperatively with PB2-627K in infected patients for optimal human adaptation.

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