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MBE Advance Access published online on June 3, 2009
Molecular Biology and Evolution, doi:10.1093/molbev/msp111
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© The Author 2009. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Research Article

Viral resistance evolution fully escapes a rationally-designed lethal inhibitor

Thomas E. Keller1, Ian J. Molineux2,3 and James J. Bull1,3,4

1 Section of Integrative Biology
2 Section of Molecular Genetics and Microbiology
3 Institute for Cellular and Molecular Biology
4 Center for Computational Biology and Bioinformatics, The University of Texas at Austin, Austin, TX 78712

Corresponding Author: Thomas E. Keller, The University of Texas at Austin, Section of Integrative Biology, One University Station, Austin, Tx 78712-0900, Phone: (512) 232-6283, Fax: (512) 471-3878, Email: tkeller{at}mail.utexas.edu

Received for publication January 12, 2009. Revision received May 17, 2009. Accepted for publication May 22, 2009.

Viruses are notoriously capable of evolving resistance to drugs. However, if the endpoint of resistance evolution is only partial escape, a feasible strategy should to be stack drugs, so the combined effect of partial inhibition by several drugs results in net inhibition. Assessing the feasibility of this approach requires quantitative data on viral fitness before and after evolution of resistance to a drug, as done here with bacteriophage T7. An inhibitory gene expressed from a phage promoter aborts wild-type T7 infections. The effect is so severe that the phage population declines when exposed to the inhibitor but expands a billion-fold per hour in its absence. In prior work, T7 evolved modest resistance to this inhibitor, an expected result. Given the nature of the inhibitor, that it used the phage's own promoter to target the phage's destruction, we anticipated that resistance evolution would be limited as the phage may need to evolve a new regulatory system, with simultaneous changes in its RNA polymerase and many of its promoters to fully escape inhibition. We show here that further adaptation of the partially resistant phage led to complete resistance. Resistance evolution was due to three mutations in the RNA polymerase gene and two other genes; unexpectedly, no changes were observed in promoters. Consideration of other mechanisms of T7 inhibition leaves hope that permanent inhibition of viral growth with drugs can in principle be achieved.

Key Words: drug resistance • experimental evolution • T7 bacteriophage • microbe • viral adaptation


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