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Journal of Virology, February 2007, p. 1274-1287, Vol. 81, No. 3
0022-538X/07/$08.00+0     doi:10.1128/JVI.00803-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Hypervariable Region within the 3' cis-Acting Element of the Murine Coronavirus Genome Is Nonessential for RNA Synthesis but Affects Pathogenesis{triangledown}

Scott J. Goebel,1 Timothy B. Miller,1 Corey J. Bennett,1 Kristen A. Bernard,1,2 and Paul S. Masters1,2*

Wadsworth Center, New York State Department of Health,1 Department of Biomedical Sciences, State University of New York, Albany, New York 122012

Received 19 April 2006/ Accepted 27 October 2006

The 3' cis-acting element for mouse hepatitis virus (MHV) RNA synthesis resides entirely within the 301-nucleotide 3' untranslated region (3' UTR) of the viral genome and consists of three regions. Encompassing the upstream end of the 3' UTR are a bulged stem-loop and an overlapping RNA pseudoknot, both of which are essential to MHV and common to all group 2 coronaviruses. At the downstream end of the genome is the minimal signal for initiation of negative-strand RNA synthesis. Between these two ends is a hypervariable region (HVR) that is only poorly conserved between MHV and other group 2 coronaviruses. Paradoxically, buried within the HVR is an octanucleotide motif (oct), 5'-GGAAGAGC-3', which is almost universally conserved in coronaviruses and is therefore assumed to have a critical biological function. We conducted an extensive mutational analysis of the HVR. Surprisingly, this region tolerated numerous deletions, rearrangements, and point mutations. Most striking, a mutant deleted of the entire HVR was only minimally impaired in tissue culture relative to the wild type. By contrast, the HVR deletion mutant was highly attenuated in mice, causing no signs of clinical disease and minimal weight loss compared to wild-type virus. Correspondingly, replication of the HVR deletion mutant in the brains of mice was greatly reduced compared to that of the wild type. Our results show that neither the HVR nor oct is essential for the basic mechanism of MHV RNA synthesis in tissue culture. However, the HVR appears to play a significant role in viral pathogenesis.

* Corresponding author. Mailing address: David Axelrod Institute, Wadsworth Center, NYSDOH, New Scotland Avenue, P.O. Box 22002, Albany, NY 12201-2002. Phone: (518) 474-1283. Fax: (518) 473-1326. E-mail: masters{at}wadsworth.org.

{triangledown} Published ahead of print on 8 November 2006.

Journal of Virology, February 2007, p. 1274-1287, Vol. 81, No. 3
0022-538X/07/$08.00+0     doi:10.1128/JVI.00803-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Zust, R., Miller, T. B., Goebel, S. J., Thiel, V., Masters, P. S. (2008). Genetic Interactions between an Essential 3' cis-Acting RNA Pseudoknot, Replicase Gene Products, and the Extreme 3' End of the Mouse Coronavirus Genome. J. Virol. 82: 1214-1228 [Abstract] [Full Text]  
  • Beerens, N., Snijder, E. J. (2007). An RNA Pseudoknot in the 3' End of the Arterivirus Genome Has a Critical Role in Regulating Viral RNA Synthesis. J. Virol. 81: 9426-9436 [Abstract] [Full Text]  
  • Brown, C. G., Nixon, K. S., Senanayake, S. D., Brian, D. A. (2007). An RNA Stem-Loop within the Bovine Coronavirus nsp1 Coding Region Is a cis-Acting Element in Defective Interfering RNA Replication. J. Virol. 81: 7716-7724 [Abstract] [Full Text]  


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