RESUMO
Oseltamivir-resistant H1N1 influenza viruses emerged in 2007 to 2008 and have subsequently circulated widely. However, prior to 2007 to 2008, viruses possessing the neuraminidase (NA) H274Y mutation, which confers oseltamivir resistance, generally had low growth capability. NA mutations that compensate for the deleterious effect of the NA H274Y mutation have since been identified. Given the importance of the functional balance between hemagglutinin (HA) and NA, we focused on amino acid changes in HA. Reverse genetic analysis showed that a mutation at residue 82, 141, or 189 of the HA protein promotes virus replication in the presence of the NA H274Y mutation. Our findings thus identify HA mutations that contributed to the replacement of the oseltamivir-sensitive viruses of 2007 to 2008.
Assuntos
Substituição de Aminoácidos , Antivirais/farmacologia , Farmacorresistência Viral , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H1N1/fisiologia , Influenza Humana/virologia , Oseltamivir/farmacologia , Replicação Viral , Sequência de Aminoácidos , Substituição de Aminoácidos/efeitos dos fármacos , Animais , Linhagem Celular , Farmacorresistência Viral/efeitos dos fármacos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Humanos , Vírus da Influenza A Subtipo H1N1/classificação , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/genética , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Neuraminidase/genética , Neuraminidase/metabolismo , Filogenia , Alinhamento de Sequência , Proteínas Virais/genética , Proteínas Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
Surveillance studies of the influenza viruses circulating in Europe and other countries in 2007 and 2008 have revealed rates of resistance to oseltamivir of up to 67% among H1N1 viruses. In the present study, we examined 202 clinical samples obtained from patients infected with H1N1 virus in Japan in 2007 and 2008 for oseltamivir resistance and found that three were oseltamivir resistant (1.5%). The 50% inhibitory concentrations (IC(50)s), as measured by a sialidase inhibition assay with these drug-resistant viruses, were >100-fold higher than those of the nonresistant viruses (median IC(50), 12.6 nmol/liter). The His274Tyr (strain N2 numbering) mutation of the neuraminidase protein, which is known to confer oseltamivir resistance, was detected in these three isolates. Phylogenetic analysis showed that one virus belonged to a lineage that is composed of drug-resistant viruses isolated in Europe and North America and that the other two viruses independently emerged in Japan. Continued surveillance studies are necessary to observe whether these viruses will persist.