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Journal of Virology, November 2009, p. 11746-11750, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01297-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Viral Adaptation to an Antiviral Protein Enhances the Fitness Level to Above That of the Uninhibited Wild Type{triangledown}

James E. Cherwa Jr.,1 Pablo Sanchez-Soria,1 Members of the University of Arizona Virology Laboratory Course 2007,1 Holly A. Wichman,2 and Bentley A. Fane1*

Department of Plant Sciences and the BIO5 Institute, University of Arizona, Tucson, Arizona 85719,1 Department of Biological Sciences, University of Idaho, Moscow, Idaho 838442

Received 24 June 2009/ Accepted 26 August 2009

Viruses often evolve resistance to antiviral agents. While resistant strains are able to replicate in the presence of the agent, they generally exhibit lower fitness than the wild-type strain in the absence of the inhibitor. In some cases, resistant strains become dependent on the antiviral agent. However, the agent rarely, if ever, elevates dependent strain fitness above the uninhibited wild-type level. This would require an adaptive mechanism to convert the antiviral agent into a beneficial growth factor. Using an inhibitory scaffolding protein that specifically blocks {phi}X174 capsid assembly, we demonstrate that such mechanisms are possible. To obtain the quintuple-mutant resistant strain, the wild-type virus was propagated for approximately 150 viral life cycles in the presence of increasing concentrations of the inhibitory protein. The expression of the inhibitory protein elevated the strain's fitness significantly above the uninhibited wild-type level. Thus, selecting for resistance coselected for dependency, which was characterized and found to operate on the level of capsid nucleation. To the best of our knowledge, this is the first report of a virus evolving a mechanism to productively utilize an antiviral agent to stimulate its fitness above the uninhibited wild-type level. The results of this study may be predictive of the types of resistant phenotypes that could be selected by antiviral agents that specifically target capsid assembly.

* Corresponding author. Mailing address: The BIO5 Institute, Keating Building, University of Arizona, Tucson, AZ 85719. Phone: (520) 626-6634. Fax: (520) 621-6366. E-mail: bfane{at}u.arizona.edu

{triangledown} Published ahead of print on 2 September 2009.

Journal of Virology, November 2009, p. 11746-11750, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01297-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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