JVI Accepts, published online ahead of print on 21 July 2010

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J. Virol. doi:10.1128/JVI.00296-10
Copyright (c) 2010, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Antiviral Susceptibility of Avian and Swine Influenza of the N1 Neuraminidase Subtype

Terri D. Stoner, Scott Krauss, Rebecca M. DuBois, Nicholas J. Negovetich, David E. Stallknecht, Dennis A. Senne, Marie R. Gramer, Seth Swafford, Tom DeLiberto, Elena A. Govorkova, and Robert G. Webster^*

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105; Southeastern Cooperative Wildlife Diseases Study, Department of Population Health, College of Veterinary Medicine, The University of Georgia, Athens, Georgia 30602; United States Department of Agriculture-National Veterinary Services Laboratories, Diagnostic Virology Section-USDA-APHIS, Ames, Iowa 50010; The University of Minnesota, College of Veterinary Medicine-Minnesota Veterinary Diagnostic and Production Animal Medicine, St. Paul, Minnesota 55108; United States Department of Agriculture-Animal and Plant Health Inspection Service, Wildlife Services-National Wildlife Disease Program

^* To whom correspondence should be addressed. Email: robert.webster{at}stjude.org.

Influenza viruses of the N1 neuraminidase (NA) subtype affecting both animals and humans caused the 2009 pandemic. Anti-influenza NA inhibitors are crucial early in a pandemic when specific influenza vaccines are unavailable. Thus, it is urgent to confirm the antiviral susceptibility of the avian viruses, a potential source of a pandemic virus. We evaluated the NA inhibitor susceptibility of viruses of the N1 subtype isolated from wild waterbirds, swine, and humans. Most avian viruses were highly or moderately susceptible to oseltamivir (IC₅₀ <5.1–50 nM). Of 91 avian isolates, 7 (7.7%) had reduced susceptibility (IC₅₀>50 nM), but were sensitive to NA inhibitors zanamivir and peramivir. Oseltamivir susceptibility ranged more widely among the waterbird viruses (IC₅₀, 0.5-154.43 nM) than among swine and human viruses (IC₅₀, 0.33-2.56 nM). Swine viruses were sensitive to oseltamivir, compared to human seasonal H1N1 isolated before 2007 (mean IC₅₀, 1.4 nM). Avian viruses from 2007-2008 were sensitive to oseltamivir, in contrast to the emergence of resistant H1N1 in humans. Susceptibility remained high to moderate over time among influenza viruses. Sequence analysis of the outliers did not detect molecular markers of drug-resistance (e.g. H275Y NA mutation, N1 numbering) but revealed mutations outside the NA active site. In particular, V267I, N307D, and V321I residue changes were found, and structural analyses suggest that these mutations distort hydrophobic pockets and affect residues in the NA active site. We determined that natural oseltamivir resistance among swine and wild waterbirds is rare. Minor naturally occurring variants in NA can affect antiviral susceptibility.