title: The K526R substitution in viral protein PB2 enhances the effects of E627K on influenza virus replication.
abstract: Host-adaptive strategies, such as the E627K substitution in the PB2 protein, are critical for replication of avian influenza A viruses in mammalian hosts. Here we show that mutation PB2-K526R is present in some human H7N9 influenza isolates, in nearly 80% of H5N1 human isolates from Indonesia and, in conjunction with E627K, in almost all seasonal H3N2 viruses since 1970. Polymerase complexes containing PB2-526R derived from H7N9, H5N1 or H3N2 viruses exhibit increased polymerase activity. PB2-526R also enhances viral transcription and replication in cells. In comparison with viruses carrying 627K, H7N9 viruses carrying both 526R and 627K replicate more efficiently in mammalian (but not avian) cells and in mouse lung tissues, and cause greater body weight loss and mortality in infected mice. PB2-K526R interacts with nuclear export protein and our results suggest that it contributes to enhance replication for certain influenza virus subtypes, particularly in combination with 627K.
authors.affiliation: 1] State Key Laboratory for Emerging Infectious Diseases, Department of Microbiology, and the Research Center of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China [2] The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Song
authors.affiliation: 1] State Key Laboratory for Emerging Infectious Diseases, Department of Microbiology, and the Research Center of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China [2] The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China.
authors.forename: Pui
authors.initials: P
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Emerging Infectious Diseases, Department of Microbiology, and the Research Center of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Bobo Wing-Yee
authors.initials: BW
authors.lastname: Mok
authors.affiliation: State Key Laboratory for Emerging Infectious Diseases, Department of Microbiology, and the Research Center of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Siu-Ying
authors.initials: SY
authors.lastname: Lau
authors.affiliation: State Key Laboratory for Emerging Infectious Diseases, Department of Microbiology, and the Research Center of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Huang
authors.affiliation: State Key Laboratory for Emerging Infectious Diseases, Department of Microbiology, and the Research Center of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Wai-Lan
authors.initials: WL
authors.lastname: Wu
authors.affiliation: State Key Laboratory for Emerging Infectious Diseases, Department of Microbiology, and the Research Center of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.affiliation: State Key Laboratory for Emerging Infectious Diseases, Department of Microbiology, and the Research Center of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wen
authors.affiliation: 1] The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China [2] State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China.
authors.forename: Shigui
authors.initials: S
authors.lastname: Yang
authors.affiliation: 1] The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China [2] State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 1] The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China [2] State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China.
authors.forename: Lanjuan
authors.initials: L
authors.lastname: Li
authors.affiliation: 1] State Key Laboratory for Emerging Infectious Diseases, Department of Microbiology, and the Research Center of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China [2] The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China.
authors.forename: Kwok-Yung
authors.initials: KY
authors.lastname: Yuen
authors.affiliation: 1] State Key Laboratory for Emerging Infectious Diseases, Department of Microbiology, and the Research Center of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China [2] The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China.
authors.forename: Honglin
authors.initials: H
authors.lastname: Chen
mesh_terms: D000818:Animals; D001483:Base Sequence; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics*; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics*; D064766:Influenza A Virus, H7N9 Subtype / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics*
chemical_list: C057027:PB2 protein, Influenzavirus A; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase