title: Oseltamivir-resistant pandemic A/H1N1 virus is as virulent as its wild-type counterpart in mice and ferrets.
abstract: The neuraminidase inhibitor oseltamivir is currently used for treatment of patients infected with the pandemic A/H1N1 (pH1N1) influenza virus, although drug-resistant mutants can emerge rapidly and possibly be transmitted. We describe the characteristics of a pair of oseltamivir-resistant and oseltamivir-susceptible pH1N1 clinical isolates that differed by a single change (H274Y) in the neuraminidase protein. Viral fitness of pH1N1 isolates was assessed in vitro by determining replication kinetics in MDCK alpha2,6 cells and in vivo by performing experimental infections of BALB/c mice and ferrets. Despite slightly reduced propagation of the mutant isolate in vitro during the first 24 h, the wild-type (WT) and mutant resistant viruses induced similar maximum weight loss in mice and ferrets with an identical pyrexic response in ferrets (AUC of 233.9 and 233.2, P = 0.5156). Similarly, comparable titers were obtained for the WT and the mutant strains on days 1, 3, 6 and 9 post-infection in mouse lungs and on days 1-7 in ferret nasal washes. A more important perivascular (day 6) and pleural (days 6 and 12) inflammation was noted in the lungs of mice infected with the H274Y mutant, which correlated with increased pulmonary levels of IL-6 and KC. Such increased levels of IL-6 were also observed in lymph nodes of ferrets infected with the mutant strain. Furthermore, the H274Y mutant strain was transmitted to ferrets. In conclusion, viral fitness of the H274Y pH1N1 isolate is not substantially altered and has the potential to induce severe disease and to disseminate.
authors.affiliation: CHUQ-CHUL Research Center in Infectious Diseases and Laval University, Québec City, Québec, Canada.
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Hamelin
authors.forename: Mariana
authors.initials: M
authors.lastname: Baz
authors.forename: Yacine
authors.initials: Y
authors.lastname: Abed
authors.forename: Christian
authors.initials: C
authors.lastname: Couture
authors.forename: Philippe
authors.initials: P
authors.lastname: Joubert
authors.forename: Edith
authors.initials: E
authors.lastname: Beaulieu
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bellerose
authors.forename: Martin
authors.initials: M
authors.lastname: Plante
authors.forename: Corey
authors.initials: C
authors.lastname: Mallett
authors.forename: Gregg
authors.initials: G
authors.lastname: Schumer
authors.forename: Gary P
authors.initials: GP
authors.lastname: Kobinger
authors.forename: Guy
authors.initials: G
authors.lastname: Boivin
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D004285:Dogs; D024882:Drug Resistance, Viral / Q000235:genetics*; D005289:Ferrets; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics* / Q000472:pathogenicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D020125:Mutation, Missense; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000235:genetics; D053139:Oseltamivir / Q000494:pharmacology*; D014774:Virulence / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D053139:Oseltamivir; D009439:Neuraminidase