This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Severson, W. E.
Right arrow Articles by Jonsson, C. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Severson, W. E.
Right arrow Articles by Jonsson, C. B.

 Previous Article  |  Next Article 

Journal of Virology, January 2003, p. 481-488, Vol. 77, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.1.481-488.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Ribavirin Causes Error Catastrophe during Hantaan Virus Replication

William E. Severson,1 Connie S. Schmaljohn,2 Ali Javadian,3,{dagger} and Colleen B. Jonsson1*

Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico 88003,1 Virology Division, U.S. Army Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland 21702,2 Coulston Foundation, Alamogordo, New Mexico 883103

Received 9 July 2002/ Accepted 30 September 2002

Except for ribavirin, no other antiviral drugs for treating hantaviral diseases have been identified. It is well established that ribavirin will inhibit the production of infectious Hantaan virus (HTNV); however, its mechanism of action is unknown. To characterize the inhibitory effect of ribavirin on HTNV, the levels of viral RNAs, proteins, and infectious particles were measured for 3 days posttreatment of HTNV-infected Vero E6 cells. HTNV-infected cells treated with ribavirin showed a slight reduction in the levels of cRNA, viral RNA, and mRNA populations on the first day postinfection. The amount of cRNA and viral RNA increased to that observed for untreated HTNV-infected cells on day 2, whereas mRNA levels were more greatly reduced on days 2 and 3. Despite the finding of S-segment mRNA, albeit low, three of the viral proteins—nucleocapsid (N) protein and glycoproteins G1 and G2—could not be detected by immunohistochemistry in ribavirin-treated cells. To test the hypothesis that these effects were caused by incorporation of ribavirin into nascent RNA and a resultant "error catastrophe" was occurring, we cloned and sequenced the S-segment cRNA/mRNA from ribavirin-treated or untreated cells from day 3. We found a high mutation frequency (9.5/1,000 nucleotides) in viral RNA synthesized in the presence of ribavirin. Hence, the transcripts produced in the presence of the drug were not functional. These results suggest that ribavirin's mechanism of action lies in challenging the fidelity of the hantavirus polymerase, which causes error catastrophe.

* Corresponding author. Mailing address: Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM 88003. Phone: (505) 646-3346. Fax: (505) 646-2649. E-mail: cjonsson{at}nmsu.edu.

{dagger} Present address: Wyeth-Lederle Vaccines, Wyeth Pharmaceuticals, Pearl River, NY 10965.

Journal of Virology, January 2003, p. 481-488, Vol. 77, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.1.481-488.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Grande-Perez, A., Lazaro, E., Lowenstein, P., Domingo, E., Manrubia, S. C. (2005). Suppression of viral infectivity through lethal defection. Proc. Natl. Acad. Sci. USA 102: 4448-4452 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»