Effect of the neuraminidase mutation H274Y conferring resistance to oseltamivir on the replicative capacity and virulence of old and recent human influenza A(H1N1) viruses.
BACKGROUND
The viral fitness of neuraminidase inhibitor (NAI)-resistant influenza viruses is believed to be impaired. Unexpectedly, an oseltamivir-resistant A(H1N1) variant containing the H274Y neuraminidase (NA) mutation recently disseminated worldwide, suggesting that the replication and virulence properties of this mutant virus were not compromised.


METHODS
In vitro replicative capacities were determined for old (A/WSN/33, A/Mississipi/3/01, A/New Caledonia/20/99, and A/Solomon Islands/03/06) and recent (A/Brisbane/59/2007-like) influenza A(H1N1) viruses either harboring or not harboring the H274Y NA mutation. Ferrets were infected with the A/Brisbane/59/2007-like wild-type (WT) isolate and its H274Y NA variant.


RESULTS
Old A(H1N1) WT viruses grew at higher titers than did the A/Brisbane/59/2007-like viruses in vitro. The H274Y mutation was associated with reduced viral plaque areas in cells infected with A/WSN/33 and A/Mississippi/3/01, whereas the 2 A/Brisbane/59/2007-like isolates showed similar plaque sizes. In ferrets, the pyrexic response induced by the A/Brisbane/59/2007-like H274Y mutant was significantly higher than that induced by the WT isolate. Nasal wash viral titers were significantly greater for the mutant isolate on day 2 after inoculation, whereas the 2 viruses showed similar titers between days 3 and 7 after inoculation.


CONCLUSIONS
The viral fitness of the recent A/Brisbane/59/2007-like H274Y variant is not impaired, consistent with its global dissemination. These results reinforce the need for new antiviral strategies.
Baz
Mariana
M
Research Center in Infectious Diseases of the Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Quebec, Canada.
Abed
Yacine
Y
Simon
Philippe
P
Hamelin
Marie-Eve
ME
Boivin
Guy
G
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D024882:Drug Resistance, Viral; D005289:Ferrets; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity*; D020125:Mutation, Missense; D009296:Nasal Cavity / Q000821:virology; D009439:Neuraminidase / Q000235:genetics*; D009976:Orthomyxoviridae Infections / Q000473:pathology / Q000821:virology; D053139:Oseltamivir / Q000494:pharmacology*; D010948:Viral Plaque Assay; D014774:Virulence; D014779:Virus Replication
D000998:Antiviral Agents; D053139:Oseltamivir; D009439:Neuraminidase