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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
general
I223R mutation in influenza A(H1N1)pdm09 neuraminidase confers reduced susceptibility to oseltamivir and zanamivir and enhanced resistance with H275Y
PLoS ONE, Volume 7, No. 8, Article e37095, Year 2012
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Description
Background: Resistance of pandemic A(H1N1)2009 (H1N1pdm09) virus to neuraminidase inhibitors (NAIs) has remained limited. A new mutation I223R in the neuraminidase (NA) of H1N1pdm09 virus has been reported along with H275Y in immunocompromised patients. The aim of this study was to determine the impact of I223R on oseltamivir and zanamivir susceptibility. Methods: The NA enzymatic characteristics and susceptibility to NAIs of viruses harbouring the mutations I223R and H275Y alone or in combination were analyzed on viruses produced by reverse genetics and on clinical isolates collected from an immunocompromised patient with sustained influenza H1N1pdm09 virus shedding and treated by oseltamivir (days 0-15) and zanamivir (days 15-25 and 70-80). Results: Compared with the wild type, the NA of recombinant viruses and clinical isolates with H275Y or I223R mutations had about two-fold reduced affinity for the substrate. The H275Y and I223R isolates showed decreased susceptibility to oseltamivir (246-fold) and oseltamivir and zanamivir (8.9- and 4.9-fold), respectively. Reverse genetics assays confirmed these results and further showed that the double mutation H275Y and I223R conferred enhanced levels of resistance to oseltamivir and zanamivir (6195- and 15.2-fold). In the patient, six days after initiation of oseltamivir therapy, the mutation H275Y conferring oseltamivir resistance and the I223R mutation were detected in the NA. Mutations were detected concomitantly from day 6-69 but molecular cloning did not show any variant harbouring both mutations. Despite cessation of NAI treatment, the mutation I223R persisted along with additional mutations in the NA and the hemagglutinin. Conclusions: Reduced susceptibility to both oseltamivir and zanamivir was conferred by the I223R mutation which potentiated resistance to both NAIs when associated with the H275Y mutation in the NA. Concomitant emergence of the I223R and H275Y mutations under oseltamivir treatment underlines the importance of close monitoring of treated patients especially those immunocompromised. © 2012 LeGoff et al.
Authors & Co-Authors
Le-Goff, Jérôme
France, Paris
Université Paris Cité
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
France, Paris
Inserm
Rousset, Dominique
France, Paris
Génétique Moléculaire Des Virus à Arn
France, Paris
Cnrs Centre National de la Recherche Scientifique
Scemla, Anne
France, Paris
Hôpital Saint-louis
Ribaud, Patricia
France, Paris
Hôpital Saint-louis
Mercier-Delarue, Séverine
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
France, Paris
Inserm
Caro, Valérie
France, Paris
Institut Pasteur, Paris
Enouf, Vincent V.E.
France, Paris
Génétique Moléculaire Des Virus à Arn
France, Paris
Cnrs Centre National de la Recherche Scientifique
Simon, Franćois
France, Paris
Université Paris Cité
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
France, Paris
Inserm
Molina, Jean Michel
France, Paris
Hôpital Saint-louis
Van Der Werf, Sylvie
France, Paris
Université Paris Cité
France, Paris
Génétique Moléculaire Des Virus à Arn
France, Paris
Cnrs Centre National de la Recherche Scientifique
Statistics
Citations: 43
Authors: 10
Affiliations: 7
Identifiers
Doi:
10.1371/journal.pone.0037095
ISSN:
19326203
Research Areas
Cancer
Genetics And Genomics
Health System And Policy