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Journal of Virology, June 2002, p. 5784-5792, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5784-5792.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Evolution of Bacteriophage in Continuous Culture: a Model System To Test Antiviral Gene Therapies for the Emergence of Phage Escape Mutants

Björn F. Lindemann,1,{dagger} Christian Klug,2 and Andreas Schwienhorst1,2*

Department of Biochemical Kinetics, Max Planck Institute for Biophysical Chemistry,1 Department for Molecular Genetics and Preparative Molecular Biology, Institute for Microbiology and Genetics, Göttingen, Germany2

Received 27 December 2001/ Accepted 17 February 2002

The emergence of viral escape mutants is usually a highly undesirable phenomenon. This phenomenon is frequently observed in antiviral drug applications for the treatment of viral infections and can undermine long-term therapeutic success. Here, we propose a strategy for evaluating a given antiviral approach in terms of its potential to provoke the appearance of resistant virus mutants. By use of Qß RNA phage as a model system, the effect of an antiviral gene therapy, i.e., a virus-specific repressor protein expressed by a recombinant Escherichia coli host, was studied over the course of more than 100 generations. In 13 experiments carried out in parallel, 12 phage populations became resistant and 1 became extinct. Sequence analysis revealed that only two distinct phage mutants emerged in the 12 surviving phage populations. For both escape mutants, sequence variations located in the repressor binding site of the viral genomic RNA, which decrease affinity for the repressor protein, conferred resistance to translational repression. The results clearly suggest the feasibility of the proposed strategy for the evaluation of antiviral approaches in terms of their potential to allow resistant mutants to appear. In addition, the strategy proved to be a valuable tool for observing virus-specific molecular targets under the impact of antiviral drugs.

* Corresponding author. Mailing address: Abteilung fuer Molekulare Genetik und Praeparative Molekularbiologie, Institut fuer Mikrobiologie und Genetik, Grisebachstr. 8, 37077 Göttingen, Germany. Phone: 49-551-393822. Fax: 49-551-393805. E-mail: aschwie1{at}gwdg.de.

{dagger} Present address: BioAgency AG, 20251 Hamburg, Germany.

Journal of Virology, June 2002, p. 5784-5792, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5784-5792.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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