title: Molecular mechanism of the enhanced viral fitness contributed by secondary mutations in the hemagglutinin protein of oseltamivir resistant H1N1 influenza viruses: modeling studies of antibody and receptor binding.
abstract: The envelope protein hemagglutinin (HA) of influenza viruses is primarily associated with host antibody and receptor interactions. The HA protein is known to maintain a functional balance with neuraminidase (NA), the other major envelope protein. Prior to 2007-2008, human seasonal H1N1 viruses possessing the NA H274Y mutation, which confers oseltamivir resistance, generally had low growth capability. Subsequently, secondary mutations that compensate for the deleterious effect of the NA H274Y mutation have been identified. The molecular mechanism of how the defect could be counteracted by these secondary mutations is not fully understood. We studied here the effect of three such mutations (T86K, K144E and R192K) in the HA protein, which are located at either the HA receptor binding site or in the H1N1 antigenic sites. Molecular docking and dynamics studies showed that, of the three mutations, the R192K mutation could have mediated neutralizing antibody escape and decreased receptor binding affinity, either or both of which may have contributed to increased viral fitness. The study suggests the molecular basis of enhanced viral fitness induced by secondary mutations in the evolution of oseltamivir-resistant influenza strains.
authors.affiliation: Bioinformatics Group, National Institute of Virology, 20-A, Dr. Ambedkar Road, Post Box No. 11, Pune 411001, Maharashtra, India. Electronic address: b.abhisekkumar@gmail.com.
authors.forename: Abhisek Kumar
authors.initials: AK
authors.lastname: Behera
authors.affiliation: Bioinformatics Group, National Institute of Virology, 20-A, Dr. Ambedkar Road, Post Box No. 11, Pune 411001, Maharashtra, India. Electronic address: sushmita.basu49@gmail.com.
authors.forename: Sushmita
authors.initials: S
authors.lastname: Basu
authors.affiliation: Bioinformatics Group, National Institute of Virology, 20-A, Dr. Ambedkar Road, Post Box No. 11, Pune 411001, Maharashtra, India. Electronic address: sarahcherian@icmr.org.in.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Cherian
mesh_terms: D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D000915:Antibody Affinity / Q000235:genetics / Q000276:immunology; D000998:Antiviral Agents / Q000494:pharmacology*; D001666:Binding Sites, Antibody / Q000235:genetics / Q000276:immunology; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral / Q000235:genetics*; D056084:Genetic Fitness; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics*; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009439:Neuraminidase / Q000235:genetics; D053139:Oseltamivir / Q000494:pharmacology*; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000998:Antiviral Agents; C543345:H1N1 virus hemagglutinin; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D053139:Oseltamivir; D009439:Neuraminidase
keywords: Antibody and receptor docking; H1N1 influenza A; Hemagglutinin; Molecular dynamics simulations; Neuraminidase H274Y mutation; Oseltamivir resistance