title: The 2008-2009 H1N1 influenza virus exhibits reduced susceptibility to antibody inhibition: Implications for the prevalence of oseltamivir resistant variant viruses.
abstract: A naturally-occurring H275Y oseltamivir resistant variant of influenza A (H1N1) virus emerged in 2007, subsequently becoming prevalent worldwide, via an undetermined mechanism. To understand the antigenic properties of the H275Y variant, oseltamivir resistant and susceptible strains of H1N1 viruses were analyzed by hemagglutination inhibition (HI) and microneutralization assays. HI analysis with H1-positive sera obtained from seasonal flu vaccine immunized and non-immunized individuals, and H1-specific monoclonal antibodies, revealed that resistant strains exhibited a reduced reactivity to these antisera and antibodies in the HI assay, as compared to susceptible strains. Neutralization assay testing demonstrated that oseltamivir resistant H1N1 strains are also less susceptible to antibody inhibition during infection. Mice inoculated with a resistant clinical isolate exhibit 4-fold lower virus-specific antibody titers than mice infected with a susceptible strain under the same conditions. Resistant and sensitive variants of 2009 pandemic H1N1 virus did not exhibit such differences. While HA1 and NA phylogenetic trees show that both oseltamivir resistant and susceptible strains belong to clade 2B, NA D354G and HA A189T substitutions were found exclusively, and universally, in oseltamivir resistant variants. Our results suggest that the reduced susceptibility to antibody inhibition and lesser in vivo immunogenicity of the oseltamivir resistant 2008-2009 H1N1 influenza A virus is conferred by coupled NA and HA mutations, and may contribute to the prevalence of this H1N1 variant.
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 Special Administrative Region, PR China.
authors.forename: Wai Lan
authors.initials: WL
authors.lastname: Wu
authors.forename: Siu-Ying
authors.initials: SY
authors.lastname: Lau
authors.forename: Yixin
authors.initials: Y
authors.lastname: Chen
authors.forename: Genyan
authors.initials: G
authors.lastname: Wang
authors.forename: Bobo Wing-Yee
authors.initials: BW
authors.lastname: Mok
authors.forename: Xi
authors.initials: X
authors.lastname: Wen
authors.forename: Pui
authors.initials: P
authors.lastname: Wang
authors.forename: Wenjun
authors.initials: W
authors.lastname: Song
authors.forename: Tianwei
authors.initials: T
authors.lastname: Lin
authors.forename: Kwok-Hung
authors.initials: KH
authors.lastname: Chan
authors.forename: Kwok-Yung
authors.initials: KY
authors.lastname: Yuen
authors.forename: Honglin
authors.initials: H
authors.lastname: Chen
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009154:Mutation; D009439:Neuraminidase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D053139:Oseltamivir / Q000494:pharmacology*; D010802:Phylogeny; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D014764:Viral Proteins; D053139:Oseltamivir; C487630:NA protein, influenza A virus; D009439:Neuraminidase