title: Quantifying relative within-host replication fitness in influenza virus competition experiments.
abstract: Through accumulation of genetic mutations in the neuraminidase gene, the influenza virus can become resistant to antiviral drugs such as oseltamivir. Quantifying the fitness of emergent drug-resistant influenza viruses, relative to contemporary circulating viruses, provides valuable information to complement existing efforts in the surveillance of drug-resistance. We have previously developed a co-infection based method for the assessment of the relative in vivo fitness of two competing viruses. We have also introduced a model of within-host co-infection dynamics that enables relative within-host fitness to be quantified in these competitive-mixtures experiments. The model assumed that fitness differences between co-infecting strains were mediated by strain-dependent viral production rates from infected epithelial cells. Here we extend the model to enable a more complete exploration of biological processes that may differ between virus pairs and hence generate fitness differences. We use the extended model to re-analyse data from competitive-mixtures experiments that investigated the fitness of oseltamivir-resistant (OR) H1N1 pandemic 2009 ("H1N1pdm09") viruses that emerged during a community outbreak in Australia in 2011. Results are consistent with those of our previous analysis, suggesting that the within-host replication fitness of these OR viruses is not compromised relative to that of related oseltamivir-susceptible (OS) strains, and that potentially permissive mutations in the neuraminidase gene (V241I and N369K) significantly enhance the fitness of H1N1pdm09 OR viruses. These results are consistent regardless of the hypothesised biological cause of fitness difference.
authors.affiliation: Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia; Centre for Transformative Innovation, Swinburne University of Technology, Hawthorn, Victoria, Australia.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Petrie
authors.affiliation: WHO Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Jeff
authors.initials: J
authors.lastname: Butler
authors.affiliation: WHO Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; School of Applied Sciences, Monash University, Churchill, Victoria, Australia.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Barr
authors.affiliation: Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia; Murdoch Childrens Research Institute, The Royal Children׳s Hospital, Parkville, Victoria, Australia.
authors.forename: Jodie
authors.initials: J
authors.lastname: McVernon
authors.affiliation: WHO Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; School of Applied Sciences, Monash University, Churchill, Victoria, Australia.
authors.forename: Aeron C
authors.initials: AC
authors.lastname: Hurt
authors.affiliation: Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia; Murdoch Childrens Research Institute, The Royal Children׳s Hospital, Parkville, Victoria, Australia; School of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: jamesm@unimelb.edu.au.
authors.forename: James M
authors.initials: JM
authors.lastname: McCaw
mesh_terms: D019943:Amino Acid Substitution; D004196:Disease Outbreaks; D005814:Genes, Viral; D054884:Host-Pathogen Interactions / Q000502:physiology*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D007251:Influenza, Human / Q000453:epidemiology / Q000821:virology*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009439:Neuraminidase / Q000235:genetics; D014779:Virus Replication / Q000502:physiology*
chemical_list: D009439:Neuraminidase
keywords: Drug-resistance; Influenza; Mathematical model; Pathogen fitness; Viral kinetics