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Title: Estimating the Fitness Advantage Conferred by Permissive Neuraminidase Mutations in Recent Oseltamivir-Resistant A(H1N1)pdm09 Influenza Viruses
Authors: Butler J.
Hooper K.A.
Petrie S.
Lee R.
Maurer-Stroh S. 
Reh L.
Guarnaccia T.
Baas C.
Xue L.
Vitesnik S.
Leang S.-K.
McVernon J.
Kelso A.
Barr I.G.
McCaw J.M.
Bloom J.D.
Hurt A.C.
Keywords: DNA fragment
virus sialidase
antivirus agent
NA protein, influenza A virus
virus protein
2009 H1N1 influenza
clinical article
clinical feature
controlled study
disease course
disease transmission
drug resistance
enzyme activity
enzyme inhibition assay
gene amplification
gene mutation
human cell
in vitro study
mathematical model
protein expression
quantitative analysis
reverse transcription polymerase chain reaction
RNA extraction
sequence analysis
site directed mutagenesis
virus replication
amino acid substitution
antagonists and inhibitors
antiviral resistance
Influenza virus A H1N1
Influenza, Human
MDCK cell line
missense mutation
reproductive fitness
Amino Acid Substitution
Antiviral Agents
Drug Resistance, Viral
Genetic Fitness
Influenza A Virus, H1N1 Subtype
Influenza, Human
Madin Darby Canine Kidney Cells
Mutation, Missense
Viral Proteins
Issue Date: 2014
Citation: Butler J., Hooper K.A., Petrie S., Lee R., Maurer-Stroh S., Reh L., Guarnaccia T., Baas C., Xue L., Vitesnik S., Leang S.-K., McVernon J., Kelso A., Barr I.G., McCaw J.M., Bloom J.D., Hurt A.C. (2014). Estimating the Fitness Advantage Conferred by Permissive Neuraminidase Mutations in Recent Oseltamivir-Resistant A(H1N1)pdm09 Influenza Viruses. PLoS Pathogens 10 (4) : e1004065. ScholarBank@NUS Repository.
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. ? 2014 Butler et al.
Source Title: PLoS Pathogens
ISSN: 15537366
DOI: 10.1371/journal.ppat.1004065
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