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Journal of Virology, January 2008, p. 246-253, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.01787-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Accelerated Evolution of Maribavir Resistance in a Cytomegalovirus Exonuclease Domain II Mutant{triangledown}

Sunwen Chou1,2* and Gail I. Marousek2

Division of Infectious Diseases, Oregon Health and Science University,1 Department of Veterans Affairs Medical Center, Portland, Oregon2

Received 15 August 2007/ Accepted 10 October 2007

A human cytomegalovirus (CMV) UL54 pol exonuclease domain II mutation, D413A, found in a clinical specimen, conferred ganciclovir (GCV) and cidofovir resistance but not foscarnet resistance when incorporated into laboratory strain T2294. After several passages without drug, mutation was observed in five of eight plaques of T2294, and its plating efficiency under foscarnet was increased ~30-fold over that of a control strain. When T2294 was serially passed under maribavir (MBV), phenotypic changes and viral UL97 mutations were detected by passage 5, much earlier than previously reported for other CMV strains. By passage 15, mutations included two cases of H411Y, one each of H411L and H411N, three of T409M, five of V353A, and one of L397R. Five instances of codon 409 or 411 mutations evolved into double mutations including V353A. Marker transfer experiments showed H411N/Y/L to confer 9- to 70-fold-increased MBV resistance and combinations of H411L/Y and V353A to confer >150-fold-increased MBV resistance, but no GCV resistance. These findings are consistent with defective exonuclease activity of the pol D413A mutant T2294, leading to the accelerated evolution of UL97 mutations under MBV. This recapitulated the known resistance mutations V353A, L397R, and T409M; suggested their relative frequency; and identified new ones at codon 411. These UL97 mutations predict an MBV binding region overlapping the kinase ATP binding site and located upstream of known GCV resistance mutations. The existence of viable pol D413A mutants may facilitate the selection of additional drug resistance mutations in vivo and the study of these mutations in vitro.

* Corresponding author. Mailing address: VA Medical Center P3ID, 3710 SW U.S. Veterans Hospital Road, Portland, OR 97239. Phone: (503) 273-5115. Fax: (503) 273-5116. E-mail: chous{at}ohsu.edu

{triangledown} Published ahead of print on 17 October 2007.

Journal of Virology, January 2008, p. 246-253, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.01787-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Wang, F.-Z., Roy, D., Gershburg, E., Whitehurst, C. B., Dittmer, D. P., Pagano, J. S. (2009). Maribavir Inhibits Epstein-Barr Virus Transcription in Addition to Viral DNA Replication. J. Virol. 83: 12108-12117 [Abstract] [Full Text]  
  • Chou, S. (2009). Diverse Cytomegalovirus UL27 Mutations Adapt to Loss of Viral UL97 Kinase Activity under Maribavir. Antimicrob. Agents Chemother. 53: 81-85 [Abstract] [Full Text]  
  • Trofe, J., Pote, L., Wade, E., Blumberg, E., Bloom, R. D (2008). Maribavir: A Novel Antiviral Agent with Activity Against Cytomegalovirus. The Annals of Pharmacotherapy 42: 1447-1457 [Abstract] [Full Text]  


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