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Journal of Virology, December 2005, p. 15314-15322, Vol. 79, No. 24
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.24.15314-15322.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Soluble Receptor-Mediated Targeting of Mouse Hepatitis Coronavirus to the Human Epidermal Growth Factor Receptor

T. Würdinger,^1,2, M. H. Verheije,^1,2, K. Broen,¹ B. J. Bosch,¹ B. J. Haijema,¹ C. A. M. de Haan,¹ V. W. van Beusechem,² W. R. Gerritsen,² and P. J. M. Rottier^1*

Virology Division, Department of Infectious Diseases & Immunology, Utrecht University, 3584 CL Utrecht,¹ Division of Gene Therapy, Department of Medical Oncology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands²

Received 5 August 2005/ Accepted 27 September 2005

The mouse hepatitis coronavirus (MHV) infects murine cells by binding of its spike (S) protein to murine CEACAM1a. The N-terminal part of this cellular receptor (soR) is sufficient for S binding and for subsequent induction of the conformational changes required for virus-cell membrane fusion. Here we analyzed whether these characteristics can be used to redirect MHV to human cancer cells. To this end, the soR domain was coupled to single-chain monoclonal antibody 425, which is directed against the human epidermal growth factor receptor (EGFR), resulting in a bispecific adapter protein (soR-425). The soR and soR-425 proteins, both produced with the vaccinia virus system, were able to neutralize MHV infection of murine LR7 cells. However, only soR-425 was able to target MHV to human EGFR-expressing cancer cells. Interestingly, the targeted infections induced syncytium formation. Furthermore, the soR-425-mediated infections were blocked by heptad repeat-mimicking peptides, indicating that virus entry requires the regular S protein fusion process. We conclude that the specific spike-binding property of the CEACAM1a N-terminal fragment can be exploited to direct the virus to selected cells by linking it to a moiety able to bind a receptor on those cells. This approach might be useful in the development of tumor-targeted coronaviruses.

T.W. and M.H.V. contributed equally to this work.

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