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Antimicrobial Agents and Chemotherapy, November 2005, p. 4515-4520, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4515-4520.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Susceptibilities of Antiviral-Resistant Influenza Viruses to Novel Neuraminidase Inhibitors

Vasiliy P. Mishin,1,{dagger} Frederick G. Hayden,1,2 and Larisa V. Gubareva1*

Division of Infectious Diseases and International Health, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia,1 Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, Virginia2

Received 9 March 2005/ Returned for modification 12 May 2005/ Accepted 16 August 2005

The susceptibilities of five zanamivir-resistant and six oseltamivir-resistant influenza viruses were assessed against four neuraminidase (NA) inhibitors, including peramivir and A-315675, by a fluorometric NA activity inhibition assay. The enzyme activity of a majority of the variants was effectively inhibited by either A-315675 or both peramivir and A-315675 (50% inhibitory concentration, <10 nM). A novel oseltamivir-resistant influenza virus B variant carrying substitution at residue 198 (Asp->Asn) (N2 numbering) retained susceptibility to peramivir and A-315675. In vivo, the Asn198 variant showed no apparent fitness impairment as judged by its recovery on day 5 from the nasal washes of ferrets coinfected with equal doses of the wild-type virus and the Asn198 variant. Based on the sequence analysis of the virus in the nasal washes, oseltamivir treatment (5 mg/kg twice daily for 5 days) did not provide growth advantage to the Asn198 variant. Nevertheless, treatment with A-315675 (prodrug A-322278) reduced the number of the animals (two of seven) shedding the Asn198 variant. These studies indicate that different patterns of susceptibility and cross-resistance between NA inhibitors may prove important if antiviral resistance to zanamivir and oseltamivir were to emerge.

* Corresponding author. Mailing address: Department of Internal Medicine, University of Virginia, P.O. Box 800473, 1300 Jefferson Ave., Rm. 2231, Charlottesville, VA 22908. Phone: (434) 243-2705. Fax: (434) 982-0384. E-mail: LVG9B{at}virginia.edu.

{dagger} Present address: Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tenn.

Antimicrobial Agents and Chemotherapy, November 2005, p. 4515-4520, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4515-4520.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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