This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yen, H.-L.
Right arrow Articles by Govorkova, E. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yen, H.-L.
Right arrow Articles by Govorkova, E. A.

 Previous Article  |  Next Article 

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

Hui-Ling Yen,1,2 Louise M. Herlocher,2 Erich Hoffmann,1 Mikhail N. Matrosovich,3,4 Arnold S. Monto,2 Robert G. Webster,1,5 and Elena A. Govorkova1*

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.

* 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.

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.



This article has been cited by other articles:

  • Bouvier, N. M., Lowen, A. C., Palese, P. (2008). Oseltamivir-Resistant Influenza A Viruses Are Transmitted Efficiently among Guinea Pigs by Direct Contact but Not by Aerosol. J. Virol. 82: 10052-10058 [Abstract] [Full Text]  
  • Moghadas, S. M (2008). Management of drug resistance in the population: influenza as a case study. Proc R Soc B 275: 1163-1169 [Abstract] [Full Text]  
  • Yen, H.-L., Ilyushina, N. A., Salomon, R., Hoffmann, E., Webster, R. G., Govorkova, E. A. (2007). Neuraminidase Inhibitor-Resistant Recombinant A/Vietnam/1203/04 (H5N1) Influenza Viruses Retain Their Replication Efficiency and Pathogenicity In Vitro and In Vivo. J. Virol. 81: 12418-12426 [Abstract] [Full Text]  
  • Debarre, F., Bonhoeffer, S., Regoes, R. R (2007). The effect of population structure on the emergence of drug resistance during influenza pandemics. J R Soc Interface 4: 893-906 [Abstract] [Full Text]  
  • Alexander, M. E, Bowman, C. S, Feng, Z., Gardam, M., Moghadas, S. M, Rost, G., Wu, J., Yan, P. (2007). Emergence of drug resistance: implications for antiviral control of pandemic influenza. Proc R Soc B 274: 1675-1684 [Abstract] [Full Text]  
  • Yen, H.-L., Lipatov, A. S., Ilyushina, N. A., Govorkova, E. A., Franks, J., Yilmaz, N., Douglas, A., Hay, A., Krauss, S., Rehg, J. E., Hoffmann, E., Webster, R. G. (2007). Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Model. J. Virol. 81: 6890-6898 [Abstract] [Full Text]  
  • Committee on Infectious Diseases, (2007). Antiviral Therapy and Prophylaxis for Influenza in Children. Pediatrics 119: 852-860 [Abstract] [Full Text]  
  • Jones, J. C., Turpin, E. A., Bultmann, H., Brandt, C. R., Schultz-Cherry, S. (2006). Inhibition of Influenza Virus Infection by a Novel Antiviral Peptide That Targets Viral Attachment to Cells. J. Virol. 80: 11960-11967 [Abstract] [Full Text]  
  • Rameix-Welti, M. A., Agou, F., Buchy, P., Mardy, S., Aubin, J. T., Veron, M., van der Werf, S., Naffakh, N. (2006). Natural Variation Can Significantly Alter the Sensitivity of Influenza A (H5N1) Viruses to Oseltamivir. Antimicrob. Agents Chemother. 50: 3809-3815 [Abstract] [Full Text]  
  • Suzuki, Y. (2006). Natural Selection on the Influenza Virus Genome. Mol Biol Evol 23: 1902-1911 [Abstract] [Full Text]  
  • Huber, V. C., McKeon, R. M., Brackin, M. N., Miller, L. A., Keating, R., Brown, S. A., Makarova, N., Perez, D. R., MacDonald, G. H., McCullers, J. A. (2006). Distinct Contributions of Vaccine-Induced Immunoglobulin G1 (IgG1) and IgG2a Antibodies to Protective Immunity against Influenza.. CVI 13: 981-990 [Abstract] [Full Text]  
  • Yen, H.-L., Hoffmann, E., Taylor, G., Scholtissek, C., Monto, A. S., Webster, R. G., Govorkova, E. A. (2006). Importance of neuraminidase active-site residues to the neuraminidase inhibitor resistance of influenza viruses.. J. Virol. 80: 8787-8795 [Abstract] [Full Text]  
  • Maines, T. R., Chen, L.-M., Matsuoka, Y., Chen, H., Rowe, T., Ortin, J., Falcon, A., Hien, N. T., Mai, L. Q., Sedyaningsih, E. R., Harun, S., Tumpey, T. M., Donis, R. O., Cox, N. J., Subbarao, K., Katz, J. M. (2006). Lack of transmission of H5N1 avian-human reassortant influenza viruses in a ferret model. Proc. Natl. Acad. Sci. USA 103: 12121-12126 [Abstract] [Full Text]  
  • Regoes, R. R., Bonhoeffer, S. (2006). Emergence of drug-resistant influenza virus: population dynamical considerations.. Science 312: 389-391 [Abstract] [Full Text]  
  • Weinstock, D. M., Zuccotti, G. (2006). Adamantane Resistance in Influenza A. JAMA 295: 934-936 [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»