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Journal of Virology, December 2002, p. 12491-12502, Vol. 76, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.24.12491-12502.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Coronaviruses Maintain Viability despite Dramatic Rearrangements of the Strictly Conserved Genome Organization

Cornelis A. M. de Haan,1* Haukeline Volders,1 Cheri A. Koetzner,2 Paul S. Masters,2 and Peter J. M. Rottier1

Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, and Institute of Biomembranes, Utrecht University, 3584 CL Utrecht, The Netherlands,1 Wadsworth Center, New York State Department of Health, Albany, New York 122012

Received 1 May 2002/ Accepted 3 September 2002

Despite their high frequency of RNA recombination, the plus-strand coronaviruses have a characteristic, strictly conserved genome organization with the essential genes occurring in the order 5'-polymerase (pol)-S-E-M-N-3'. We have investigated the significance of this remarkable conservation by rearrangement of the murine coronavirus genome through targeted recombination. Thus, viruses were prepared with the following gene order: 5'-pol-S-M-E-N-3', 5'-pol-S-N-E-M-3', 5'-pol-M-S-E-N-3', and 5'-pol-E-M-S-N-3'. All of these viruses were surprisingly viable, and most viruses replicated in cell culture with growth characteristics similar to those of the parental virus. The recombinant virus with the gene order 5'-pol-E-M-S-N-3' was also tested for the ability to replicate in the natural host, the mouse. The results indicate that the canonical coronavirus genome organization is not essential for replication in vitro and in vivo. Deliberate rearrangement of the viral genes may be useful in the generation of attenuated coronaviruses, which due to their reduced risk of generating viable viruses by recombination with circulating field viruses, would make safer vaccines.

* Corresponding author. Mailing address: Virology Division, Department of Infectious Diseases and Immunology, Yalelaan 1, 3584CL Utrecht, The Netherlands. Phone: 31-30-3524195. Fax: 31-30-2536723. E-mail: x.haan{at}vet.uu.nl.

Journal of Virology, December 2002, p. 12491-12502, Vol. 76, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.24.12491-12502.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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