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Molecular mechanisms underlying oseltamivir resistance mediated by an I117V substitution in the neuraminidase of subtype H5N1 avian influenza A viruses.

ABSTRACT: BACKGROUND: The neuraminidase (NA) inhibitor oseltamivir is widely used to treat patients infected with influenza viruses. An Ile-to-Val change at position 117 in influenza A virus subtype H5N1 NA (NA-I117V) confers a reduction in susceptibility to oseltamivir carboxylate. However, the in vivo relevance and molecular basis of the decreased sensitivity mediated by this mutation are poorly understood. METHODS: We created single-point-mutant viruses with 3 genetically different backgrounds (ie, 1 belonging to clade 1 and 2 belonging to clade 2.3.4) and evaluated the effects of the I117V mutation on oseltamivir susceptibility in vitro, in vivo, and in silico. RESULTS: The NA-I117V mutation conferred a slight reduction in susceptibility to oseltamivir in vitro (1.3- to 6.3-fold changes), although it did not substantially compromise NA enzymatic activity. Mice infected with I117V virus exhibited reduced susceptibility to oseltamivir and decreased survival in 2 of 3 virus pairs tested. Molecular dynamics simulations revealed that I117V caused the loss of hydrogen bonds between an arginine at position 118 and the carboxyl group of oseltamivir, leading to a lower binding affinity for oseltamivir. CONCLUSIONS: Our findings provide new insight into the mechanism of NA-I117V-mediated oseltamivir resistance in highly pathogenic H5N1 avian influenza viruses.

SUBMITTER: Takano R

PROVIDER: S-EPMC3571237 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Molecular mechanisms underlying oseltamivir resistance mediated by an I117V substitution in the neuraminidase of subtype H5N1 avian influenza A viruses.

Takano Ryo R Kiso Maki M Igarashi Manabu M Le Quynh Mai QM Sekijima Masakazu M Ito Kimihito K Takada Ayato A Kawaoka Yoshihiro Y

The Journal of infectious diseases 20121010 1

<h4>Background</h4>The neuraminidase (NA) inhibitor oseltamivir is widely used to treat patients infected with influenza viruses. An Ile-to-Val change at position 117 in influenza A virus subtype H5N1 NA (NA-I117V) confers a reduction in susceptibility to oseltamivir carboxylate. However, the in vivo relevance and molecular basis of the decreased sensitivity mediated by this mutation are poorly understood.<h4>Methods</h4>We created single-point-mutant viruses with 3 genetically different backgro ...[more]

PMID: 23053629

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Project description:BackgroundOngoing outbreaks of H5N1 highly pathogenic avian influenza (HPAI) viruses and the emergence of the genetic-related hemagglutinin (HA) gene of reassortant H5Nx viruses currently circulating in wild birds and poultries pose a great global public health concern. In this study, we comprehensively analyzed the genetic evolution of Thai H5N1 HA and neuraminidase (NA) genes between 2003 and 2010. The H5N1 Thailand virus clade 2.3.4 was also genetically compared to the currently circulating clade 2.3.4.4 of H5Nx viruses.MethodsFull-length nucleotide sequences of 178 HA and 143 NA genes of H5N1 viruses circulating between 2003 and 2010 were phylogenetically analyzed using maximum likelihood (ML) phylogenetic construction. Bayesian phylogenetic trees were reconstructed using BEAST analysis with a Bayesian Markov chain Monte Carlo (MCMC) approach. The maximum clade credibility (MCC) tree was determined, and the time of the most recent common ancestor (tMRCA) was estimated. The H5N1 HA nucleotide sequences of clade 2.3.4 Thailand viruses were phylogenetically analyzed using ML phylogenetic tree construction and analyzed for nucleotide similarities with various subtypes of reassortant H5Nx HA clade 2.3.4.4.ResultsML phylogenetic analysis revealed two distinct HA clades, clade 1 and clade 2.3.4, and two distinct NA groups within the corresponding H5 clade 1 viruses. Bayesian phylogenetic reconstruction for molecular clock suggested that the Thai H5N1 HA and NA emerged in 2001.87 (95% HPD: 2001.34-2002.49) and 2002.38 (95% HPD: 2001.99-2002.82), respectively, suggesting that the virus existed before it was first reported in 2004. The Thai H5N1 HA clade 2.3.4 was grouped into corresponding clades 2.3.4, 2.3.4.1, 2.3.4.2, and 2.3.4.3, and shared nucleotide similarities to reassortant H5Nx clade 2.3.4.4 ranged from 92.4-96.8%. Phylogenetic analysis revealed monophyletic H5Nx clade 2.3.4.4 evolved from H5N1 clade 2.3.4.ConclusionH5N1 viruses existed, and were presumably introduced and circulated in avian species in Thailand, before they were officially reported in 2004. HA and NA genes continuously evolved during circulation between 2004 and 2010. This study provides a better understanding of genetic evolution with respect to molecular epidemiology. Monitoring and surveillance of emerging variants/reassortants should be continued.

Dataset Information

Molecular mechanisms underlying oseltamivir resistance mediated by an I117V substitution in the neuraminidase of subtype H5N1 avian influenza A viruses.

Publications

Molecular mechanisms underlying oseltamivir resistance mediated by an I117V substitution in the neuraminidase of subtype H5N1 avian influenza A viruses.

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