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Journal of Virology, June 1999, p. 4705-4712, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Phenotypic Consequences of Rearranging the P, M, and G Genes of Vesicular Stomatitis Virus

L. Andrew Ball,1,* Craig R. Pringle,2 Brian Flanagan,1 Victoria P. Perepelitsa,1 and Gail W. Wertz1

Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294,1 and Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, England2

Received 8 February 1999/Accepted 9 March 1999

The nonsegmented negative-strand RNA viruses (order Mononegavirales) include many important human pathogens. The order of their genes, which is highly conserved, is the major determinant of the relative levels of gene expression, since genes that are close to the single promoter site at the 3' end of the viral genome are transcribed at higher levels than those that occupy more distal positions. We manipulated an infectious cDNA clone of the prototypic vesicular stomatitis virus (VSV) to rearrange three of the five viral genes, using an approach which left the viral nucleotide sequence otherwise unaltered. The central three genes in the gene order, which encode the phosphoprotein P, the matrix protein M, and the glycoprotein G, were rearranged into all six possible orders. Viable viruses were recovered from each of the rearranged cDNAs. The recovered viruses were examined for their levels of gene expression, growth potential in cell culture, and virulence in mice. Gene rearrangement changed the expression levels of the encoded proteins in concordance with their distance from the 3' promoter. Some of the viruses with rearranged genomes replicated as well or slightly better than wild-type virus in cultured cells, while others showed decreased replication. All of the viruses were lethal for mice, although the time to symptoms and death following inoculation varied. These data show that despite the highly conserved gene order of the Mononegavirales, gene rearrangement is not lethal or necessarily even detrimental to the virus. These findings suggest that the conservation of the gene order observed among the Mononegavirales may result from immobilization of the ancestral gene order due to the lack of a mechanism for homologous recombination in this group of viruses. As a consequence, gene rearrangement should be irreversible and provide an approach for constructing viruses with novel phenotypes.

* Corresponding author. Mailing address: Microbiology Department, UAB, BBRB 373/17, 845 19th St. South, Birmingham, AL 35294. Phone: (205) 934-0864. Fax: (205) 934-1636. E-mail: Andyb{at}uab.edu.

Journal of Virology, June 1999, p. 4705-4712, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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