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Journal of Virology, September 2006, p. 8787-8795, Vol. 80, No. 17
0022-538X/06/$08.00+0     doi:10.1128/JVI.00477-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Importance of Neuraminidase Active-Site Residues to the Neuraminidase Inhibitor Resistance of Influenza Viruses

Hui-Ling Yen,1,2 Erich Hoffmann,1 Garry Taylor,3 Christoph Scholtissek,1 Arnold S. Monto,2 Robert G. Webster,1,4 and Elena A. Govorkova1*

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,1 Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan 48109,2 Centre for Biomolecular Sciences, University of St. Andrews, St. Andrews, Fife KY16 9ST, Scotland, United Kingdom,3 Department of Pathology, University of Tennessee, Memphis, Tennessee 381054

Received 7 March 2006/ Accepted 7 June 2006

Neuraminidase inhibitors (NAIs) are antivirals designed to target conserved residues at the neuraminidase (NA) enzyme active site in influenza A and B viruses. The conserved residues that interact with NAIs are under selective pressure, but only a few have been linked to resistance. In the A/Wuhan/359/95 (H3N2) recombinant virus background, we characterized seven charged, conserved NA residues (R118, R371, E227, R152, R224, E276, and D151) that directly interact with the NAIs but have not been reported to confer resistance to NAIs. These NA residues were replaced with amino acids that possess side chains having similar properties to maintain their original charge. The NA mutations we introduced significantly decreased NA activity compared to that of the A/Wuhan/359/95 recombinant wild-type and R292K (an NA mutation frequently reported to confer resistance) viruses, which were analyzed for comparison. However, the recombinant viruses differed in replication efficiency when we serially passaged them in vitro; the growth of the R118K and E227D viruses was most impaired. The R224K, E276D, and R371K mutations conferred resistance to both zanamivir and oseltamivir, while the D151E mutation reduced susceptibility to oseltamivir only (~10-fold) and the R152K mutation did not alter susceptibility to either drug. Because the R224K mutation was genetically unstable and the emergence of the R371K mutation in the N2 subtype is statistically unlikely, our results suggest that only the E276D mutation is likely to emerge under selective pressure. The results of our study may help to optimize the design of NAIs.

* Corresponding author. Mailing address: Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794. Phone: (901) 495-2243. Fax: (901) 523-2622. E-mail: elena.govorkova{at}stjude.org.

Journal of Virology, September 2006, p. 8787-8795, Vol. 80, No. 17
0022-538X/06/$08.00+0     doi:10.1128/JVI.00477-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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