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Journal of Virology, March 2008, p. 2580-2585, Vol. 82, No. 5
0022-538X/08/$08.00+0     doi:10.1128/JVI.02287-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Coronavirus Escape from Heptad Repeat 2 (HR2)-Derived Peptide Entry Inhibition as a Result of Mutations in the HR1 Domain of the Spike Fusion Protein

Berend Jan Bosch,¹ John W. A. Rossen,^2, Willem Bartelink,¹ Stephanie J. Zuurveen,² Cornelis A. M. de Haan,¹ Stephane Duquerroy,³ Charles A. B. Boucher,² and Peter J. M. Rottier^1*

Virology Division, Department of Infectious Diseases and Immunology, Utrecht University, Faculty of Veterinary Medicine, and Institute of Biomembranes, Yalelaan 1, 3584 CL Utrecht, The Netherlands,¹ Eijkman-Winkler Centre for Microbiology, Infectious Diseases and Inflammation, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands,² Unité de Virologie Structurale, Département de Virologie, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France³

Received 22 October 2007/ Accepted 5 December 2007

Peptides based on heptad repeat (HR) domains of class I viral fusion proteins are considered promising antiviral drugs targeting virus cell entry. We have analyzed the evolution of the mouse hepatitis coronavirus during multiple passaging in the presence of an HR2-based fusion inhibitor. Drug-resistant variants emerged as a result of multiple substitutions in the spike fusion protein, notably within a 19-residue segment of the HR1 region. Strikingly, one mutation, an A1006V substitution, which consistently appeared first in four independently passaged viruses, was the main determinant of the resistance phenotype, suggesting that only limited options exist for escape from the inhibitory effect of the HR2 peptide.

Published ahead of print on 12 December 2007.

Present address: St. Elisabeth Hospital, Laboratory of Medical Microbiology and Immunology, Hilvarenbeekseweg 60, 5022 GC Tilburg, The Netherlands.