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Journal of Virology, October 2009, p. 10366-10373, Vol. 83, No. 20
0022-538X/09/$08.00+0     doi:10.1128/JVI.01200-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Zanamivir-Resistant Influenza Viruses with a Novel Neuraminidase Mutation{triangledown}

Aeron C. Hurt,1,2* Jessica K. Holien,3 Michael Parker,3,4 Anne Kelso,1 and Ian G. Barr1,2

WHO Collaborating Centre for Reference and Research on Influenza, 10 Wreckyn Street, North Melbourne, Victoria 3051, Australia,1 Monash University, School of Applied Sciences, Churchill, Victoria 3842, Australia,2 Structural Biology Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia,3 Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3052, Australia4

Received 11 June 2009/ Accepted 21 July 2009

The neuraminidase inhibitors zanamivir and oseltamivir are marketed for the treatment and prophylaxis of influenza and have been stockpiled by many countries for use in a pandemic. Although recent surveillance has identified a striking increase in the frequency of oseltamivir-resistant seasonal influenza A (H1N1) viruses in Europe, the United States, Oceania, and South Africa, to date there have been no reports of significant zanamivir resistance among influenza A (H1N1) viruses or any other human influenza viruses. We investigated the frequency of oseltamivir and zanamivir resistance in circulating seasonal influenza A (H1N1) viruses in Australasia and Southeast Asia. Analysis of 391 influenza A (H1N1) viruses isolated between 2006 and early 2008 from Australasia and Southeast Asia revealed nine viruses (2.3%) that demonstrated markedly reduced zanamivir susceptibility and contained a previously undescribed Gln136Lys (Q136K) neuraminidase mutation. The mutation had no effect on oseltamivir susceptibility but caused approximately a 300-fold and a 70-fold reduction in zanamivir and peramivir susceptibility, respectively. The role of the Q136K mutation in conferring zanamivir resistance was confirmed using reverse genetics. Interestingly, the mutation was not detected in the primary clinical specimens from which these mutant isolates were grown, suggesting that the resistant viruses either occurred in very low proportions in the primary clinical specimens or arose during MDCK cell culture passage. Compared to susceptible influenza A (H1N1) viruses, the Q136K mutant strains displayed greater viral fitness than the wild-type virus in MDCK cells but equivalent infectivity and transmissibility in a ferret model.

* Corresponding author. Mailing address: WHO Collaborating Centre for Reference and Research on Influenza, 10 Wreckyn St., North Melbourne, Victoria 3051, Australia. Phone: 613 9342 3914. Fax: 613 9342 3939. E-mail: aeron.hurt{at}influenzacentre.org

{triangledown} Published ahead of print on 29 July 2009.

Journal of Virology, October 2009, p. 10366-10373, Vol. 83, No. 20
0022-538X/09/$08.00+0     doi:10.1128/JVI.01200-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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