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Journal of Virology, June 2006, p. 5697-5707, Vol. 80, No. 12
0022-538X/06/$08.00+0     doi:10.1128/JVI.02729-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Mutations in Influenza Virus M1 CCHH, the Putative Zinc Finger Motif, Cause Attenuation in Mice and Protect Mice against Lethal Influenza Virus Infection

Eric Ka-Wai Hui,1 Donald F. Smee,2 Min-Hui Wong,2 and Debi P. Nayak1*

Department of Microbiology, Immunology, and Molecular Genetics, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, David Geffen School of Medicine, UCLA, Los Angeles, California 90095-1747,1 Department of Animal, Dairy, and Veterinary Sciences, Institute for Antiviral Research, Utah State University, Logan, Utah 84322-56002

Received 28 December 2005/ Accepted 20 March 2006

Mutations in CCHH, the putative zinc finger motif, apparently do not play an important role in virus replication in MDCK cells in culture (E. K.-W. Hui, K. Ralston, A. K. Judd, and D. P. Nayak, J. Gen. Virol. 84:3105-3113, 2003). In this report, however, we demonstrate that the CCHH motif plays a critical role in virulence in mice and that some CCHH mutants are highly attenuated in BALB/c mice. Some of the mutant viruses replicated the least in mice lungs, induced little or no lung lesions, and caused highly reduced morbidity and mortality. Furthermore, growth patterns of mutant viruses in different cell lines (MDCK, MLE12, 3LL, A549, and 293T) varied. Mutant viruses that were attenuated in mice also grew poorly in mouse and human cells in culture. However, wild-type (WT) and all mutant viruses replicated to the same titer in MDCK (canine) cells or embryonated chicken eggs. Attenuation in mice correlated with reduced growth in mouse cells in culture, suggesting that potential attenuation in a given host can be predicted from the growth characteristics of the virus in cultured cells (preferably lung cells) from the same species. In challenge experiments, mice immunized by infection with attenuated mutant viruses were fully protected from lethal challenge with WT virus. In summary, the replication and attenuating properties of these mutants suggest that the CCHH motif provides a critical determinant for virulence in mouse and that mutations in the CCHH motif yield potential vaccine candidates for the development of live species-specific attenuated influenza virus vaccines.

* Corresponding author. Mailing address: Department of Microbiology, Immunology, and Molecular Genetics, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, David Geffen School of Medicine, UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095-1747. Phone: (310) 825-8558. Fax: (310) 206-3865. E-mail: dnayak{at}ucla.edu.

Journal of Virology, June 2006, p. 5697-5707, Vol. 80, No. 12
0022-538X/06/$08.00+0     doi:10.1128/JVI.02729-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





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