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Journal of Virology, June 2005, p. 6940-6946, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.6940-6946.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Attenuation of Bunyavirus Replication by Rearrangement of Viral Coding and Noncoding Sequences

Anice C. Lowen,1 Amanda Boyd,2 John K. Fazakerley,2 and Richard M. Elliott1*

Division of Virology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G11 5JR, Scotland, United Kingdom,1 Centre for Infectious Diseases, College of Medicine and Veterinary Medicine, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, Scotland, United Kingdom2

Received 30 November 2004/ Accepted 28 January 2005

Bunyamwera virus (BUN) is the prototype virus of the family Bunyaviridae. BUN has a tripartite negative-sense RNA genome comprising small (S), medium (M), and large (L) segments. Partially complementary untranslated regions (UTRs) flank the coding region of each segment. The terminal 11 nucleotides of these UTRs are conserved between the three segments, while the internal regions are unique. The UTRs direct replication and transcription of viral RNA and are sufficient to allow encapsidation of viral RNA into ribonucleoprotein complexes. To investigate the segment-specific functions of the UTRs, we have used reverse genetics to recover a recombinant virus (called BUN MLM) in which the L segment open reading frame (ORF) is flanked by the M segment UTRs. Compared to wild-type virus, BUN MLM virus shows growth attenuation in cultured mammalian cells and a slower disease progression in mice, produces small plaques, expresses reduced levels of L mRNA and L (RNA polymerase) protein, synthesizes less L genomic and antigenomic RNA, and has an increased particle-to-PFU ratio. Our data suggest that the packaging of BUN RNAs is not segment specific. In addition, the phenotype of BUN MLM virus supports the finding that BUN UTRs differ in their regulation of RNA synthesis but suggests that the interplay between each segment UTR and its cognate ORF may contribute to that regulation. Since BUN MLM virus is attenuated due to an essentially irreversible mutation, the rearrangement of UTRs is a feasible strategy for vaccine design for the more pathogenic members of the Bunyaviridae.

* Corresponding author. Mailing address: Institute of Virology, University of Glasgow, Church St., Glasgow G11 5JR, Scotland, United Kingdom. Phone: 44 141 330 4024. Fax: 44 141 337 2236. E-mail: elliott{at}vir.gla.ac.uk.

Journal of Virology, June 2005, p. 6940-6946, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.6940-6946.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Eifan, S. A., Elliott, R. M. (2009). Mutational Analysis of the Bunyamwera Orthobunyavirus Nucleocapsid Protein Gene. J. Virol. 83: 11307-11317 [Abstract] [Full Text]  
  • XU, F., LIU, D., NUNES, M. R. T., DA ROSA, A. P. A. T., TESH, R. B., XIAO, S.-Y. (2007). ANTIGENIC AND GENETIC RELATIONSHIPS AMONG RIFT VALLEY FEVER VIRUS AND OTHER SELECTED MEMBERS OF THE GENUS PHLEBOVIRUS (BUNYAVIRIDAE). Am J Trop Med Hyg 76: 1194-1200 [Abstract] [Full Text]  
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