title: Viral genetic determinants of H5N1 influenza viruses that contribute to cytokine dysregulation.
abstract: Human disease caused by highly pathogenic avian influenza (H5N1) is associated with fulminant viral pneumonia and mortality rates in excess of 60%. Cytokine dysregulation is thought to contribute to its pathogenesis. In comparison with human seasonal influenza (H1N1) viruses, clade 1, 2.1, and 2.2 H5N1 viruses induced higher levels of tumor necrosis factor-alpha in primary human macrophages. To understand viral genetic determinants responsible for this hyperinduction of cytokines, we constructed recombinant viruses containing different combinations of genes from high-cytokine (A/Vietnam/1203/04) and low-cytokine (A/WSN/33) phenotype H1N1 viruses and tested their cytokine-inducing phenotype in human macrophages. Our results suggest that the H5N1 polymerase gene segments, and to a lesser extent the NS gene segment, contribute to cytokine hyperinduction in human macrophages and that a putative H5 pandemic virus that may arise through genetic reassortment between H5N1 and one of the current seasonal influenza viruses may have a markedly altered cytokine phenotype.
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong Special Administrative Region, People's Republic of China.
authors.forename: Ka Pun
authors.initials: KP
authors.lastname: Mok
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong Special Administrative Region, People's Republic of China.
authors.forename: Charmaine H K
authors.initials: CHK
authors.lastname: Wong
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong Special Administrative Region, People's Republic of China.
authors.forename: Chung Y
authors.initials: CY
authors.lastname: Cheung
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong Special Administrative Region, People's Republic of China.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Chan
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong Special Administrative Region, People's Republic of China.
authors.forename: Suki M Y
authors.initials: SMY
authors.lastname: Lee
authors.affiliation: Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong Special Administrative Region, People's Republic of China.
authors.forename: John M
authors.initials: JM
authors.lastname: Nicholls
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong Special Administrative Region, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong Special Administrative Region, People's Republic of China.|HKU-Pasteur Research Centre, Pok Fu Lam, Hong Kong Special Administrative Region, People's Republic of China.
authors.forename: Joseph S M
authors.initials: JSM
authors.lastname: Peiris
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D006388:Hemagglutinins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D053124:Influenza A Virus, H5N1 Subtype / Q000145:classification / Q000235:genetics*; D007251:Influenza, Human / Q000821:virology; D009439:Neuraminidase / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D014764:Viral Proteins; D014779:Virus Replication
chemical_list: D016207:Cytokines; D006388:Hemagglutinins; D014764:Viral Proteins; D004259:DNA-Directed DNA Polymerase; D009439:Neuraminidase
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