Estimating the fitness advantage conferred by permissive neuraminidase mutations in recent oseltamivir-resistant A(H1N1)pdm09 influenza viruses.
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.
World Health Organization Collaborating Centre for Reference and Research on Influenza, North Melbourne, Australia.
Jeff
J
Butler
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, United States of America.
Kathryn A
KA
Hooper
Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Australia.
Stephen
S
Petrie
Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore.
Raphael
R
Lee
Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore; National Public Health Laboratory, Communicable Diseases Division Ministry of Health, Singapore; School of Biological Sciences (SBS), Nanyang Technological University (NTU), Singapore.
Sebastian
S
Maurer-Stroh
World Health Organization Collaborating Centre for Reference and Research on Influenza, North Melbourne, Australia.
Lucia
L
Reh
World Health Organization Collaborating Centre for Reference and Research on Influenza, North Melbourne, Australia.
Teagan
T
Guarnaccia
World Health Organization Collaborating Centre for Reference and Research on Influenza, North Melbourne, Australia; Monash University, School of Applied Sciences, Churchill, Victoria, Australia.
Chantal
C
Baas
World Health Organization Collaborating Centre for Reference and Research on Influenza, North Melbourne, Australia.
Lumin
L
Xue
World Health Organization Collaborating Centre for Reference and Research on Influenza, North Melbourne, Australia.
Sophie
S
Vitesnik
World Health Organization Collaborating Centre for Reference and Research on Influenza, North Melbourne, Australia.
Sook-Kwan
SK
Leang
Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Australia; Murdoch Childrens Research Institute, The Royal Children's Hospital, Melbourne, Victoria, Australia.
Jodie
J
McVernon
World Health Organization Collaborating Centre for Reference and Research on Influenza, North Melbourne, Australia.
Anne
A
Kelso
World Health Organization Collaborating Centre for Reference and Research on Influenza, North Melbourne, Australia; Monash University, School of Applied Sciences, Churchill, Victoria, Australia.
Ian G
IG
Barr
Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Australia; Murdoch Childrens Research Institute, The Royal Children's Hospital, Melbourne, Victoria, Australia.
James M
JM
McCaw
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Jesse D
JD
Bloom
World Health Organization Collaborating Centre for Reference and Research on Influenza, North Melbourne, Australia; Monash University, School of Applied Sciences, Churchill, Victoria, Australia.
Aeron C
AC
Hurt
D019943:Amino Acid Substitution; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D004285:Dogs; D024882:Drug Resistance, Viral / Q000235:genetics*; D005289:Ferrets; D056084:Genetic Fitness; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics*; D007251:Influenza, Human / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics; D061985:Madin Darby Canine Kidney Cells; D020125:Mutation, Missense; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000235:genetics*; D053139:Oseltamivir / Q000494:pharmacology*; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*
D000998:Antiviral Agents; D014764:Viral Proteins; D053139:Oseltamivir; C487630:NA protein, influenza A virus; D009439:Neuraminidase