JVI Accepts, published online ahead of print on 26 December 2007

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J. Virol. doi:10.1128/JVI.01899-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A novel approach to the development of effective H5N1 influenza A virus vaccines: the use of M2 cytoplasmic tail mutants

Tokiko Watanabe, Shinji Watanabe, Jin Hyun Kim, Masato Hatta, and Yoshihiro Kawaoka^*

Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706, USA; Division of Virology, Department of Microbiology and Immunology, and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

^* To whom correspondence should be addressed. Email: kawaokay{at}svm.vetmed.wisc.edu.

Outbreaks of highly pathogenic H5N1 influenza viruses in avian species began in Asia and have since spread to other continents. Concern regarding the pandemic potential of these viruses in humans is clearly warranted, as is the need to develop effective vaccines against them. Previously, we and others demonstrated that deletions of the M2 cytoplasmic tail caused a growth defect in A/WSN/33 (H1N1) influenza A virus in vitro (Iwatsuki-Horimoto et al., J. Virol. 80: 5233-5240, 2006; McCown and Pekosz, J. Virol. 79: 3595-3605, 2005 and J. Virol. 80: 8178-8189, 2006). We, therefore, tested the feasibility of using M2 tail mutants as live attenuated vaccines against H5N1 virus. First, we generated a series of highly pathogenic H5N1 [A/Vietnam/1203/04 (VN1203)] M2 cytoplasmic tail deletion mutants and examined their growth properties in vitro and in vivo. We found that one mutant, which contains an 11-amino-acid deletion from the C-terminus (M2del11 virus), grew as well as the wild-type virus, but replicated in mice less efficiently. We then generated a recombinant VN1203 M2del11 virus whose HA gene was modified by replacing sequences at the cleavage site with those of an avirulent type of HA (M2del11-HAavir virus). This M2del11-HAavir virus protected mice against challenge with a lethal dose of homologous [VN1203 (clade 1)] and antigenically distinct heterologous [A/Indonesia/7/2005 (clade 2)] H5N1 viruses. Our results suggest that M2 cytoplasmic tail mutants have potential as live attenuated influenza vaccines against H5N1 viruses.

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