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Journal of Virology, October 2007, p. 11413-11425, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.01287-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Signal Peptide and Helical Bundle Domains of Virulent Canine Distemper Virus Fusion Protein Restrict Fusogenicity

Philippe Plattet,¹ Pascal Cherpillod,² Dominique Wiener,¹ Ljerka Zipperle,¹ Marc Vandevelde,¹ Riccardo Wittek,³ and Andreas Zurbriggen^1*

Department of Clinical Veterinary Medicine, University of Bern, Bern, Switzerland,¹ Central Laboratory of Virology, Division of Infectious Diseases, University Hospitals of Geneva, Geneva, Switzerland,² Institut de Biotechnologie, University of Lausanne, Lausanne, Switzerland³

Received 13 June 2007/ Accepted 30 July 2007

Persistence in canine distemper virus (CDV) infection is correlated with very limited cell-cell fusion and lack of cytolysis induced by the neurovirulent A75/17-CDV compared to that of the cytolytic Onderstepoort vaccine strain. We have previously shown that this difference was at least in part due to the amino acid sequence of the fusion (F) protein (P. Plattet, J. P. Rivals, B. Zuber, J. M. Brunner, A. Zurbriggen, and R. Wittek, Virology 337:312-326, 2005). Here, we investigated the molecular mechanisms of the neurovirulent CDV F protein underlying limited membrane fusion activity. By exchanging the signal peptide between both F CDV strains or replacing it with an exogenous signal peptide, we demonstrated that this domain controlled intracellular and consequently cell surface protein expression, thus indirectly modulating fusogenicity. In addition, by serially passaging a poorly fusogenic virus and selecting a syncytium-forming variant, we identified the mutation L372W as being responsible for this change of phenotype. Intriguingly, residue L372 potentially is located in the helical bundle domain of the F₁ subunit. We showed that this mutation drastically increased fusion activity of F proteins of both CDV strains in a signal peptide-independent manner. Due to its unique structure even among morbilliviruses, our findings with respect to the signal peptide are likely to be specifically relevant to CDV, whereas the results related to the helical bundle add new insights to our growing understanding of this class of F proteins. We conclude that different mechanisms involving multiple domains of the neurovirulent A75/17-CDV F protein act in concert to limit fusion activity, preventing lysis of infected cells, which ultimately may favor viral persistence.

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* Corresponding author. Mailing address: Department of Clinical Veterinary Medicine, Bremgartenstrasse 109a, 3001 Bern, Switzerland. Phone: 4131 631 25 09. Fax: 4131 631 25 38. E-mail: andreas.zurbriggen{at}itn.unibe.ch

Published ahead of print on 8 August 2007.

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Journal of Virology, October 2007, p. 11413-11425, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.01287-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Anderson, D. E., von Messling, V. (2008). Region between the Canine Distemper Virus M and F Genes Modulates Virulence by Controlling Fusion Protein Expression. J. Virol. 82: 10510-10518 [Abstract] [Full Text]