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Estimating the fitness advantage conferred by permissive neuraminidase mutations in recent oseltamivir-resistant A(H1N1)pdm09 influenza viruses.

ABSTRACT: Oseltamivir is relied upon worldwide as the drug of choice for the treatment of human influenza infection. Surveillance for oseltamivir resistance is routinely performed to ensure the ongoing efficacy of oseltamivir against circulating viruses. Since the emergence of the pandemic 2009 A(H1N1) influenza virus (A(H1N1)pdm09), the proportion of A(H1N1)pdm09 viruses that are oseltamivir resistant (OR) has generally been low. However, a cluster of OR A(H1N1)pdm09 viruses, encoding the neuraminidase (NA) H275Y oseltamivir resistance mutation, was detected in Australia in 2011 amongst community patients that had not been treated with oseltamivir. Here we combine a competitive mixtures ferret model of influenza infection with a mathematical model to assess the fitness, both within and between hosts, of recent OR A(H1N1)pdm09 viruses. In conjunction with data from in vitro analyses of NA expression and activity we demonstrate that contemporary A(H1N1)pdm09 viruses are now more capable of acquiring H275Y without compromising their fitness, than earlier A(H1N1)pdm09 viruses circulating in 2009. Furthermore, using reverse engineered viruses we demonstrate that a pair of permissive secondary NA mutations, V241I and N369K, confers robust fitness on recent H275Y A(H1N1)pdm09 viruses, which correlated with enhanced surface expression and enzymatic activity of the A(H1N1)pdm09 NA protein. These permissive mutations first emerged in 2010 and are now present in almost all circulating A(H1N1)pdm09 viruses. Our findings suggest that recent A(H1N1)pdm09 viruses are now more permissive to the acquisition of H275Y than earlier A(H1N1)pdm09 viruses, increasing the risk that OR A(H1N1)pdm09 will emerge and spread worldwide.

SUBMITTER: Butler J

PROVIDER: S-EPMC3974874 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Estimating the fitness advantage conferred by permissive neuraminidase mutations in recent oseltamivir-resistant A(H1N1)pdm09 influenza viruses.

Butler Jeff J Hooper Kathryn A KA Petrie Stephen S Lee Raphael R Maurer-Stroh Sebastian S Reh Lucia L Guarnaccia Teagan T Baas Chantal C Xue Lumin L Vitesnik Sophie S Leang Sook-Kwan SK McVernon Jodie J Kelso Anne A Barr Ian G IG McCaw James M JM Bloom Jesse D JD Hurt Aeron C AC

PLoS pathogens 20140403 4

Oseltamivir is relied upon worldwide as the drug of choice for the treatment of human influenza infection. Surveillance for oseltamivir resistance is routinely performed to ensure the ongoing efficacy of oseltamivir against circulating viruses. Since the emergence of the pandemic 2009 A(H1N1) influenza virus (A(H1N1)pdm09), the proportion of A(H1N1)pdm09 viruses that are oseltamivir resistant (OR) has generally been low. However, a cluster of OR A(H1N1)pdm09 viruses, encoding the neuraminidase ( ...[more]

PMID: 24699865

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Project description:Oseltamivir-resistant influenza viruses arise due to amino acid mutations in key residues of the viral neuraminidase (NA). These changes often come at a fitness cost; however, it is known that permissive mutations in the viral NA can overcome this cost. This result was observed in former seasonal A(H1N1) viruses in 2007 which expressed the H275Y substitution (N1 numbering) with no apparent fitness cost and lead to widespread oseltamivir resistance. Therefore, this study aims to predict permissive mutations that may similarly enable fit H275Y variants to arise in currently circulating A(H1N1)pdm09 viruses. The first approach in this study utilized in silico analyses to predict potentially permissive mutations. The second approach involved the generation of a virus library which encompassed all possible NA mutations while keeping H275Y fixed. Fit variants were then selected by serially passaging the virus library either through ferrets by transmission or passaging once in vitro. The fitness impact of selected substitutions was further evaluated experimentally. The computational approach predicted three candidate permissive NA mutations which, in combination with each other, restored the replicative fitness of an H275Y variant. The second approach identified a stringent bottleneck during transmission between ferrets; however, three further substitutions were identified which may improve transmissibility. A comparison of fit H275Y variants in vitro and in experimentally infected animals showed a statistically significant correlation in the variants that were positively selected. Overall, this study provides valuable tools and insights into potential permissive mutations that may facilitate the emergence of a fit H275Y A(H1N1)pdm09 variant. IMPORTANCE Oseltamivir (Tamiflu) is the most widely used antiviral for the treatment of influenza infections. Therefore, resistance to oseltamivir is a public health concern. This study is important as it explores the different evolutionary pathways available to current circulating influenza viruses that may lead to widespread oseltamivir resistance. Specifically, this study develops valuable experimental and computational tools to evaluate the fitness landscape of circulating A(H1N1)pmd09 influenza viruses bearing the H275Y mutation. The H275Y substitution is most commonly reported to confer oseltamivir resistance but also leads to loss of virus replication and transmission fitness, which limits its spread. However, it is known from previous influenza seasons that influenza viruses can evolve to overcome this loss of fitness. Therefore, this study aims to prospectively predict how contemporary A(H1N1)pmd09 influenza viruses may evolve to overcome the fitness cost of bearing the H275Y NA substitution, which could result in widespread oseltamivir resistance.

Project description:BackgroundResistance 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.MethodsThe 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).ResultsCompared 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.ConclusionsReduced 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.

Dataset Information

Estimating the fitness advantage conferred by permissive neuraminidase mutations in recent oseltamivir-resistant A(H1N1)pdm09 influenza viruses.

Publications

Estimating the fitness advantage conferred by permissive neuraminidase mutations in recent oseltamivir-resistant A(H1N1)pdm09 influenza viruses.

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