title: Permissive changes in the neuraminidase play a dominant role in improving the viral fitness of oseltamivir-resistant seasonal influenza A(H1N1) strains.
abstract: Permissive neuraminidase (NA) substitutions such as R222Q, V234M and D344N have facilitated the emergence and worldwide spread of oseltamivir-resistant influenza A/Brisbane/59/2007 (H1N1)-H275Y viruses. However, the potential contribution of genetic changes in other viral segments on viral fitness remains poorly investigated. A series of recombinant A(H1N1)pdm09 and A/WSN/33 7:1 reassortants containing the wild-type (WT) A/Brisbane/59/2007 NA gene or its single (H275Y) and double (H275Y/Q222R, H275Y/M234V and H275Y/N344D) variants were generated and their replicative properties were assessed in vitro. The Q222R reversion substitution significantly reduced viral titers when evaluated in both A(H1N1)pdm09 and A/WSN/33 backgrounds. The permissive role of the R222Q was further confirmed using A/WSN/33 7:1 reassortants containing the NA gene of the oseltamivir-susceptible or oseltamivir-resistant influenza A/Mississippi/03/2001 strains. Therefore, NA permissive substitutions play a dominant role for improving viral replication of oseltamivir-resistant A (H1N1)-H275Y viruses in vitro.
authors.affiliation: Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, Québec City, QC, Canada.
authors.forename: Yacine
authors.initials: Y
authors.lastname: Abed
authors.affiliation: Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, Québec City, QC, Canada.
authors.forename: Andrés
authors.initials: A
authors.lastname: Pizzorno
authors.affiliation: Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, Québec City, QC, Canada.
authors.forename: Xavier
authors.initials: X
authors.lastname: Bouhy
authors.affiliation: Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, Québec City, QC, Canada. Electronic address: Guy.Boivin@crchul.ulaval.ca.
authors.forename: Guy
authors.initials: G
authors.lastname: Boivin
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000235:genetics*; D056084:Genetic Fitness; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D007251:Influenza, Human / Q000821:virology; D020125:Mutation, Missense; D009439:Neuraminidase / Q000235:genetics* / Q000378:metabolism; D053139:Oseltamivir / Q000494:pharmacology*; D012621:Seasons; D019562:Viral Load; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D014764:Viral Proteins; D053139:Oseltamivir; C487630:NA protein, influenza A virus; D009439:Neuraminidase
keywords: Fitness; H1N1; Influenza; Neuraminidase; Oseltamivir; Resistance