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Journal of Virology, September 2005, p. 12016-12024, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.12016-12024.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Inhibition of Coxsackie B Virus Infection by Soluble Forms of Its Receptors: Binding Affinities, Altered Particle Formation, and Competition with Cellular Receptors

Ian G. Goodfellow,1,2 David J. Evans,2 Anna M. Blom,3 Dave Kerrigan,2 J. Scott Miners,4 B. Paul Morgan,4 and O. Brad Spiller4*

School of Animal and Microbial Sciences, University of Reading, P.O. Box 228, Reading RG6 6AJ, United Kingdom,1 Division of Virology, Institute of Biomedical and Life Sciences, University of Glasgow, Church Street, Glasgow G11 5JR, United Kingdom,2 Department of Laboratory Medicine, Lund University, University Hospital Malmö, Malmö S-20502, Sweden,3 Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Henry Wellcome Building, 3rd floor, Heath Park, Cardiff CF14 4XN, United Kingdom4

Received 7 January 2005/ Accepted 13 June 2005

We previously reported that soluble decay-accelerating factor (DAF) and coxsackievirus-adenovirus receptor (CAR) blocked coxsackievirus B3 (CVB3) myocarditis in mice, but only soluble CAR blocked CVB3-mediated pancreatitis. Here, we report that the in vitro mechanisms of viral inhibition by these soluble receptors also differ. Soluble DAF inhibited virus infection through the formation of reversible complexes with CVB3, while binding of soluble CAR to CVB induced the formation of altered (A) particles with a resultant irreversible loss of infectivity. A-particle formation was characterized by loss of VP4 from the virions and required incubation of CVB3-CAR complexes at 37°C. Dimeric soluble DAF (DAF-Fc) was found to be 125-fold-more effective at inhibiting CVB3 than monomeric DAF, which corresponded to a 100-fold increase in binding affinity as determined by surface plasmon resonance analysis. Soluble CAR and soluble dimeric CAR (CAR-Fc) bound to CVB3 with 5,000- and 10,000-fold-higher affinities than the equivalent forms of DAF. While DAF-Fc was 125-fold-more effective at inhibiting virus than monomeric DAF, complement regulation by DAF-Fc was decreased 4 fold. Therefore, while the virus binding was a cooperative event, complement regulation was hindered by the molecular orientation of DAF-Fc, indicating that the regions responsible for complement regulation and virus binding do not completely overlap. Relative contributions of CVB binding affinity, receptor binding footprint on the virus capsid, and induction of capsid conformation alterations for the ability of cellular DAF and CAR to act as receptors are discussed.

* Corresponding author. Mailing address: Virus Receptor and Immune Evasion Group, School of Medicine, Cardiff University, Henry Wellcome Building, 3rd floor, Heath Park, Cardiff CF14 4XN, United Kingdom. Phone: 44 02920 742471. Fax: 44 02920 744001. E-mail: SpillerB{at}cardiff.ac.uk.

Journal of Virology, September 2005, p. 12016-12024, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.12016-12024.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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