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J. Biol. Chem., Vol. 281, Issue 14, 9200-9204, April 7, 2006

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Significant Redox Insensitivity of the Functions of the SARS-CoV Spike Glycoprotein

COMPARISON WITH HIV ENVELOPE^*

Dimitri Lavillette¹, Rym Barbouche^¶1, Yongxiu Yao^||, Bertrand Boson, François-Loïc Cosset, Ian M. Jones^||, and Emmanuel Fenouillet²

From the INSERM U758, Ecole Normale Supérieure, Institut Fédératif de Recherche (IFR) 128, Lyon-Gerland F69007, Lyon, France, IFR Jean-Roche, Faculté de Médecine Nord, F13015, Marseille, France, ^¶Institut Supérieur de Biotechnologie de Monastir, 5000 Monastir, Tunisia and ^||School of Animal and Microbial Sciences, University of Reading, RG6 6AJ Reading, England, United Kingdom

The capacity of the surface glycoproteins of enveloped viruses to mediate virus/cell binding and membrane fusion requires a proper thiol/disulfide balance. Chemical manipulation of their redox state using reducing agents or free sulfhydryl reagents affects virus/cell interaction. Conversely, natural thiol/disulfide rearrangements often occur during the cell interaction to trigger fusogenicity, hence the virus entry. We examined the relationship between the redox state of the 20 cysteine residues of the SARS-CoV (severe acute respiratory syndrome coronavirus) Spike glycoprotein S1 subdomain and its functional properties. Mature S1 exhibited 4 unpaired cysteines, and chemically reduced S1 displaying up to 6 additional unpaired cysteines still bound ACE2 and enabled fusion. In addition, virus/cell membrane fusion occurred in the presence of sulfhydryl-blocking reagents and oxidoreductase inhibitors. Thus, in contrast to various viruses including HIV (human immunodeficiency virus) examined in parallel, the functions of the SARS-CoV Spike glycoprotein exhibit a significant and surprising independence of redox state, which may contribute to the wide host range of the virus. These data suggest clues for molecularly engineering vaccine immunogens.

Received for publication, November 22, 2005 , and in revised form, January 11, 2006.

^* This work was supported in part by a grant from the Agence Nationale de Recherche sur le SIDA (ANRS) (to E. F., I. M. J., and F.-L. C.), a fellowship from the ANRS (to R. B.), European Community Contract LSHB-CT-2004-005242, a grant from CONSERT (concerted safety and efficiency of retroviral transgenesis for gene therapy of inherited disease) (to F.-L. C.), and a grant from the Biotechnology and Biological Sciences Research Council (to I. M. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² Supported by ANRS Grant HCV 2006. To whom correspondence should be addressed: Faculté de Médecine Nord, Blvd. P. Dramard, F13015 Marseille, France. Tel./Fax: 33-491-69-88-47; E-mail: fenouillet.e{at}jean-roche.univ-mrs.fr.

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