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PLoS ONE. I223R Mutation in Influenza A(H1N1)pdm09 Neuraminidase Confers Reduced Susceptibility to Oseltamivir and Zanamivir and Enhanced Resistance with H275Y
[Source: PLoS ONE, full text: (LINK). Abstract, edited.]
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I223R Mutation in Influenza A(H1N1)pdm09 Neuraminidase Confers Reduced Susceptibility to Oseltamivir and Zanamivir and Enhanced Resistance with H275Y
J?rome LeGoff<SUP>1</SUP><SUP>,</SUP><SUP>2</SUP><SUP>,</SUP><SUP>3</SUP><SUP>#</SUP>, Dominique Rousset<SUP>4</SUP><SUP>,</SUP><SUP>5</SUP><SUP>#</SUP>, Georges Abou-Jaoud?<SUP>4</SUP><SUP>,</SUP><SUP>5</SUP>, Anne Scemla<SUP>6</SUP>, Patricia Ribaud<SUP>7</SUP>, S?verine Mercier-Delarue<SUP>2</SUP><SUP>,</SUP><SUP>3</SUP>, Val?rie Caro<SUP>8</SUP>, Vincent Enouf<SUP>4</SUP><SUP>,</SUP><SUP>5</SUP>, Fran?ois Simon<SUP>1</SUP><SUP>,</SUP><SUP>2</SUP><SUP>,</SUP><SUP>3</SUP>, Jean-Michel Molina<SUP>6</SUP>, Sylvie van der Werf<SUP>1</SUP><SUP>,</SUP><SUP>4</SUP><SUP>,</SUP><SUP>5</SUP><SUP>*</SUP>
<SUP></SUP>
1 University Paris Diderot, Sorbonne Paris Cit?, Paris, France, 2 Assistance Publique-H?pitaux de Paris, Laboratoire de Microbiologie, H?pital Saint Louis, Paris, France, 3 Inserm U941, Paris, France, 4 Institut Pasteur, Unit? de G?n?tique Mol?culaire des Virus ? ARN, Centre National de R?f?rence des virus influenzae (R?gion-Nord), D?partement de Virologie, Paris, France, 5 Centre National de la Recherche Scientifique, URA3015, Paris, France, 6 Infectious Disease Department, H?pital Saint Louis, Paris, France, 7 Service d'H?matologie-Greffe, H?pital Saint Louis, Paris, France, 8 Institut Pasteur, Plateforme de g?notypage des pathog?nes et sant? publique, Paris, France
Abstract
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.
Citation: LeGoff J, Rousset D, Abou-Jaoud? G, Scemla A, Ribaud P, et al. (2012) I223R Mutation in Influenza A(H1N1)pdm09 Neuraminidase Confers Reduced Susceptibility to Oseltamivir and Zanamivir and Enhanced Resistance with H275Y. PLoS ONE 7(8): e37095. doi:10.1371/journal.pone.0037095
Editor: Paul Digard, University of Edinburgh, United Kingdom
Received: April 14, 2011; Accepted: April 17, 2012; Published: August 24, 2012
Copyright: ? 2012 LeGoff et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the Institut Pasteur, funding from the Institut de Veille Sanitaire to the National Influenza Center (Northern-France), the Centre National de la Recherche Scientifique [URA3015], the University Paris Diderot Paris 7, Assistance Publique-H?pitaux de Paris and the European Community's Seventh Framework Programme (FP7/2007?2013) under the project ?European Management Platform for Emerging and Re-emerging Infectious disease Entities? EC [grant agreement number 223498]. GAJ was supported by a grant from the United States Department of Health and Human Services. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: SvdW received research grant from Glaxo-Smith Kline-Beecham (GSK) on unrelated subject; has joined patent from institution with GSK on unrelated subject; involvement in some epidemiological studies partially or fully granted by Roche and GSK; received travel grants and honoraria to institution for speaking or participation at meetings by GSK. VE received grant for public health related study from GSK; his spouse is employed by GSK. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.
* E-mail: sylvie.van-der-werf@pasteur.fr
# These authors contributed equally to this work.
-J?rome LeGoff<SUP>1</SUP><SUP>,</SUP><SUP>2</SUP><SUP>,</SUP><SUP>3</SUP><SUP>#</SUP>, Dominique Rousset<SUP>4</SUP><SUP>,</SUP><SUP>5</SUP><SUP>#</SUP>, Georges Abou-Jaoud?<SUP>4</SUP><SUP>,</SUP><SUP>5</SUP>, Anne Scemla<SUP>6</SUP>, Patricia Ribaud<SUP>7</SUP>, S?verine Mercier-Delarue<SUP>2</SUP><SUP>,</SUP><SUP>3</SUP>, Val?rie Caro<SUP>8</SUP>, Vincent Enouf<SUP>4</SUP><SUP>,</SUP><SUP>5</SUP>, Fran?ois Simon<SUP>1</SUP><SUP>,</SUP><SUP>2</SUP><SUP>,</SUP><SUP>3</SUP>, Jean-Michel Molina<SUP>6</SUP>, Sylvie van der Werf<SUP>1</SUP><SUP>,</SUP><SUP>4</SUP><SUP>,</SUP><SUP>5</SUP><SUP>*</SUP>
<SUP></SUP>
1 University Paris Diderot, Sorbonne Paris Cit?, Paris, France, 2 Assistance Publique-H?pitaux de Paris, Laboratoire de Microbiologie, H?pital Saint Louis, Paris, France, 3 Inserm U941, Paris, France, 4 Institut Pasteur, Unit? de G?n?tique Mol?culaire des Virus ? ARN, Centre National de R?f?rence des virus influenzae (R?gion-Nord), D?partement de Virologie, Paris, France, 5 Centre National de la Recherche Scientifique, URA3015, Paris, France, 6 Infectious Disease Department, H?pital Saint Louis, Paris, France, 7 Service d'H?matologie-Greffe, H?pital Saint Louis, Paris, France, 8 Institut Pasteur, Plateforme de g?notypage des pathog?nes et sant? publique, Paris, France
Abstract
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.
Citation: LeGoff J, Rousset D, Abou-Jaoud? G, Scemla A, Ribaud P, et al. (2012) I223R Mutation in Influenza A(H1N1)pdm09 Neuraminidase Confers Reduced Susceptibility to Oseltamivir and Zanamivir and Enhanced Resistance with H275Y. PLoS ONE 7(8): e37095. doi:10.1371/journal.pone.0037095
Editor: Paul Digard, University of Edinburgh, United Kingdom
Received: April 14, 2011; Accepted: April 17, 2012; Published: August 24, 2012
Copyright: ? 2012 LeGoff et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the Institut Pasteur, funding from the Institut de Veille Sanitaire to the National Influenza Center (Northern-France), the Centre National de la Recherche Scientifique [URA3015], the University Paris Diderot Paris 7, Assistance Publique-H?pitaux de Paris and the European Community's Seventh Framework Programme (FP7/2007?2013) under the project ?European Management Platform for Emerging and Re-emerging Infectious disease Entities? EC [grant agreement number 223498]. GAJ was supported by a grant from the United States Department of Health and Human Services. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: SvdW received research grant from Glaxo-Smith Kline-Beecham (GSK) on unrelated subject; has joined patent from institution with GSK on unrelated subject; involvement in some epidemiological studies partially or fully granted by Roche and GSK; received travel grants and honoraria to institution for speaking or participation at meetings by GSK. VE received grant for public health related study from GSK; his spouse is employed by GSK. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.
* E-mail: sylvie.van-der-werf@pasteur.fr
# These authors contributed equally to this work.
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