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Antimicrobial Agents and Chemotherapy, October 2005, p. 4075-4084, Vol. 49, No. 10
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.10.4075-4084.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Neuraminidase Inhibitor-Resistant Influenza Viruses May Differ Substantially in Fitness and Transmissibility

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794,¹ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan 48109,² Institute of Virology, Philipps University, 35037 Marburg, Germany,³ M. P. Chumakov Institute of Poliomyelitis and Viral Encephalitides, Moscow 142782, Russia,⁴ Department of Pathology, University of Tennessee, Memphis, Tennessee 38105⁵

Received 20 April 2005/ Returned for modification 14 June 2005/ Accepted 14 July 2005

Mutations of the conserved residues of influenza virus neuraminidase (NA) that are associated with NA inhibitor (NAI) resistance decrease the sialidase activity and/or stability of the NA, thus compromising viral fitness. In fact, clinically derived NAI-resistant variants with different NA mutations have shown different transmissibilities in ferrets (M. L. Herlocher, R. Truscon, S. Elias, H. Yen, N. A. Roberts, S. E. Ohmit, and A. S. Monto, J. Infect. Dis. 190:1627-1630, 2004). Molecular characterization of mutant viruses that have a homogeneous genetic background is required to determine the effect of single mutations at conserved NA residues. We generated recombinant viruses containing either the wild-type NA (RG WT virus) or a single amino acid change at NA residue 119 (RG E119V-NA virus) or 292 (RG R292K-NA virus) in the A/Wuhan/359/95 (H3N2) influenza virus background by reverse genetics. Both mutants showed decreased sensitivity to oseltamivir carboxylate, and the RG R292K-NA virus showed cross-resistance to zanamivir. We also observed differences between the two mutants in NA enzymatic activity and thermostability. The R292K mutation caused greater reduction of sialidase activity and thermostability than the E119V mutation. The NA defect caused by the R292K mutation was associated with compromised growth and transmissibility, whereas the growth and transmissibility of the RG E119V-NA virus were comparable to those of RG WT virus. Our results suggest that NAI-resistant influenza virus variants may differ substantially in fitness and transmissibility, depending on different levels of NA functional loss.

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