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Journal of Virology, July 2000, p. 6015-6020, Vol. 74, No. 13
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Balanced Hemagglutinin and Neuraminidase Activities Are Critical for Efficient Replication of Influenza A Virus

Lyndon J. Mitnaul,1,dagger Mikhail N. Matrosovich,1,2 Maria R. Castrucci,3 Alexander B. Tuzikov,4 Nikolai V. Bovin,4 Darwyn Kobasa,1 and Yoshihiro Kawaoka5,6,*

Department of Virology and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 381011; M. P. Chumakov Institute of Poliomyelitis and Viral Encephalitides, Russian Academy of Medical Sciences, 142782 Moscow,2 and Shemyakin Institute of Bioorganic Chemistry, Miklukho-Maklaya, 117871 Moscow,4 Russia; Dipartimento di Virologia, Istituto Superiore di Sanita, 00161 Rome, Italy3; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin---Madison, Madison, Wisconsin 537065; and Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan6

Received 13 December 1999/Accepted 6 April 2000

The SD0 mutant of influenza virus A/WSN/33 (WSN), characterized by a 24-amino-acid deletion in the neuraminidase (NA) stalk, does not grow in embryonated chicken eggs because of defective NA function. Continuous passage of SD0 in eggs yielded 10 independent clones that replicated efficiently. Characterization of these egg-adapted viruses showed that five of the viruses contained insertions in the NA gene from the PB1, PB2, or NP gene, in the region linking the transmembrane and catalytic head domains, demonstrating that recombination of influenza viral RNA segments occurs relatively frequently. The other five viruses did not contain insertions in this region but displayed decreased binding affinity toward sialylglycoconjugates, compared with the binding properties of the parental virus. Sequence analysis of one of the latter viruses revealed mutations in the hemagglutinin (HA) gene, at sites in close proximity to the sialic acid receptor-binding pocket. These mutations appear to compensate for reduced NA function due to stalk deletions. Thus, balanced HA-NA functions are necessary for efficient influenza virus replication.

* Corresponding author. Mailing address: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin---Madison, 2015 Linden Dr. West, Madison, WI 53706. Phone: (608) 265-4925. Fax: (608) 265-5622. E-mail: kawaokay{at}svm.vetmed.wisc.edu.

dagger Present address: Department of Immunology and Rheumatology, Merck Research Laboratories, Rahway, NJ 07065.

Journal of Virology, July 2000, p. 6015-6020, Vol. 74, No. 13
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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