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Antimicrobial Agents and Chemotherapy, October 2009, p. 4457-4463, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00650-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Large-Scale Sequence Analysis of M Gene of Influenza A Viruses from Different Species: Mechanisms for Emergence and Spread of Amantadine Resistance ^,

Yuki Furuse, Akira Suzuki, and Hitoshi Oshitani^*

Department of Virology, Tohoku University Graduate School of Medicine, 2-1 Seiryou-machi Aoba-ku, Sendai, 980-8575, Japan

Received 13 May 2009/ Returned for modification 12 June 2009/ Accepted 27 July 2009

Influenza A virus infects many species, and amantadine is used as an antiviral agent. Recently, a substantial increase in amantadine-resistant strains has been reported, most of which have a substitution at amino acid position 31 in the M2 gene. Understanding the mechanism responsible for the emergence and spread of antiviral resistance is important for developing a treatment protocol for seasonal influenza and for deciding on a policy for antiviral stockpiling for pandemic influenza. The present study was conducted to identify the existence of drug pressure on the emergence and spread of amantadine-resistant influenza A viruses. We analyzed data on more than 5,000 virus sequences and constructed a phylogenetic tree to calculate selective pressures on sites in the M2 gene associated with amantadine resistance (positions 26, 27, 30, and 31) among different hosts. The phylogenetic tree revealed that the emergence and spread of the drug-resistant M gene in different hosts and subtypes were independent and not through reassortment. For human influenza virus, positive selection was detected only at position 27. Selective pressures on the sites were not always higher for human influenza virus than for viruses of other hosts. Additionally, selective pressure on position 31 did not increase after the introduction of amantadine. Although there is a possibility of drug pressure on human influenza virus, we could not find positive pressure on position 31. Because the recent rapid increase in drug-resistant virus is associated with the substitution at position 31, the resistance may not be related to drug use.

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* Corresponding author. Mailing address: Department of Virology, Tohoku University Graduate School of Medicine 2-1 Seiryou-mach, Aoba-ku, Sendai, 980-8575, Japan. Phone: 81-22-717-8211. Fax: 81-22-717-8212. E-mail: oshitanih{at}mail.tains.tohoku.ac.jp

Published ahead of print on 3 August 2009.

Supplemental material for this article may be found at http://aac.asm.org/.

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Antimicrobial Agents and Chemotherapy, October 2009, p. 4457-4463, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00650-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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