Butler J, Hooper KA, Petrie S, Lee R, Maurer-Stroh S, et al. (2014) Estimating the Fitness Advantage Conferred by Permissive Neuraminidase Mutations in Recent Oseltamivir-Resistant A(H1N1)pdm09 Influenza Viruses. PLoS Pathog 10(4): e1004065. doi:10.1371/journal.ppat.1004065
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.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health. JMM is supported by an Australian Research Council Future Fellowship (FT110100250) and the Defence Science Institute. JM is supported by a National Health and Medical Research Council Career Development Fellowship. Funding for this research was also kindly provided by the University of Melbourne Research Grants Support Scheme. JDB and KAH were supported by a grant from the NIAID of the National Institutes of Health under award K22AI093789. The authors acknowledge use of computing resources for the quantification of within-host fitness provided by the NeCTAR research cloud (an Australian Government project conducted as part of the Super Science initiative and financed by the Education Investment Fund) and by the Victorian Life Sciences Computation Initiative (VLSCI), grant number VR0274, on its Peak Computing Facility at the University of Melbourne (an initiative of the Victorian Government, Australia.). This work was partially supported by the Australian NHMRC and A*STAR Singapore through the joint grant 12/1/06/24/5793 to ACH and SMS.