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Journal of Virology, November 2007, p. 11722-11729, Vol. 81, No. 21
0022-538X/07/$08.00+0     doi:10.1128/JVI.00874-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Ribavirin Reveals a Lethal Threshold of Allowable Mutation Frequency for Hantaan Virus{triangledown}

Dong-Hoon Chung,1 Yanjie Sun,1 William B. Parker,1 Jeffrey B. Arterburn,2 Al Bartolucci,3 and Colleen B. Jonsson1*

Department of Biochemistry and Molecular Biology, 2000 9th Ave. South, Southern Research Institute, Birmingham, Alabama 35205,1 Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico 88003,2 Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama 352943

Received 24 April 2007/ Accepted 6 August 2007

The broad spectrum of antiviral activity of ribavirin (RBV) lies in its ability to inhibit IMP dehydrogenase, which lowers cellular GTP. However, RBV can act as a potent mutagen for some RNA viruses. Previously we have shown a lack of correlation between antiviral activity and GTP repression for Hantaan virus (HTNV) and evidence for RBV's ability to promote error-prone replication. To further explore the mechanism of RBV, GTP levels, specific infectivity, and/or mutation frequency was measured in the presence of RBV, mycophenolic acid (MPA), selenazofurin, or tiazofurin. While all four drugs resulted in a decrease in the GTP levels and infectious virus, only RBV increased the mutation frequency of viral RNA (vRNA). MPA, however, could enhance RBV's mutagenic effect, which suggests distinct mechanisms of action for each. Therefore, a simple drop in GTP levels does not drive the observed error-prone replication. To further explore RBV's mechanism of action, we made a comprehensive analysis of the mutation frequency over several RBV concentrations. Of importance, we observed that the viral population reached a threshold after which mutation frequency did not correlate with a dose-dependent decrease in the level of vRNA, PFU, or [RTP]/[GTP] (where RTP is ribavirin-5'-triphosphate) over these same concentrations of RBV. Modeling of the relationship of mutation frequency and drug concentration showed an asymptotic relationship at this point. After this threshold, approximately 57% of the viral cDNA population was identical to the wild type. These studies revealed a lethal threshold, after which we did not observe a complete loss of the quasispecies structure of the wild-type genome, although we observed extinction of HTNV.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, 2000 9th Ave. South, Southern Research Institute, Birmingham, AL 35205. Phone: (205) 581-2681. Fax: (205) 581-2093. E-mail: jonsson{at}sri.org

{triangledown} Published ahead of print on 15 August 2007.

Journal of Virology, November 2007, p. 11722-11729, Vol. 81, No. 21
0022-538X/07/$08.00+0     doi:10.1128/JVI.00874-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Dapp, M. J., Clouser, C. L., Patterson, S., Mansky, L. M. (2009). 5-Azacytidine Can Induce Lethal Mutagenesis in Human Immunodeficiency Virus Type 1. J. Virol. 83: 11950-11958 [Abstract] [Full Text]  
  • Bull, J. J., Wilke, C. O. (2008). Lethal Mutagenesis of Bacteria. Genetics 180: 1061-1070 [Abstract] [Full Text]  


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