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J Infect Dis. 2015 Jan 15;211(2):249-57. doi: 10.1093/infdis/jiu447. Epub 2014 Aug 14.

Characterization of drug-resistant influenza A(H7N9) variants isolated from an oseltamivir-treated patient in Taiwan.

Author information

1
Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention.
2
Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention Battelle Memorial Institute, Atlanta, Georgia.
3
Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention Oak Ridge Institute for Science and Education, Tennessee.
4
Taiwan Centers for Disease Control, Taipei City.
5
Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention lgubareva@cdc.gov.

Abstract

BACKGROUND:

Patients contracting influenza A(H7N9) infection often developed severe disease causing respiratory failure. Neuraminidase (NA) inhibitors (NAIs) are the primary option for treatment, but information on drug-resistance markers for influenza A(H7N9) is limited.

METHODS:

Four NA variants of A/Taiwan/1/2013(H7N9) virus containing a single substitution (NA-E119V, NA-I222K, NA-I222R, or NA-R292K) recovered from an oseltamivir-treated patient were tested for NAI susceptibility in vitro; their replicative fitness was evaluated in cell culture, mice, and ferrets.

RESULTS:

NA-R292K led to highly reduced inhibition by oseltamivir and peramivir, while NA-E119V, NA-I222K, and NA-I222R caused reduced inhibition by oseltamivir. Mice infected with any virus showed severe clinical signs with high mortality rates. NA-I222K virus was the most virulent in mice, whereas virus lacking NA change (NA-WT) and NA-R292K virus seemed the least virulent. Sequence analysis suggests that PB2-S714N increased virulence of NA-I222K virus in mice; NS1-K126R, alone or in combination with PB2-V227M, produced contrasting effects in NA-WT and NA-R292K viruses. In ferrets, all viruses replicated to high titers in the upper respiratory tract but produced only mild illness. NA-R292K virus, showed reduced replicative fitness in this animal model.

CONCLUSIONS:

Our data highlight challenges in assessment of the replicative fitness of H7N9 NA variants that emerged in NAI-treated patients.

KEYWORDS:

E119V; H7N9; I222K; I222R; R292K; ferrets; influenza virus; mice; oseltamivir; peramivir

PMID:
25124927
DOI:
10.1093/infdis/jiu447
[Indexed for MEDLINE]

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