Fcγ Receptor-like Activity of Hepatitis C Virus Core Protein

doi:10.1074/jbc.M311470200

Fcγ Receptor-like Activity of Hepatitis C Virus Core Protein*

^‡Carcinogénèse Hépatique et Virologie Moléculaire, ^**Unité des Venins, and ^§§Plateau Génomique Structurale, Institut Pasteur, 75724 Paris cedex 15, the ^§Institut de Biologie et Chimie des Protéines, CNRS UMR 5086, 7 Passage du Vercors, 69367 Lyon cedex 07, and ^¶INSERM U.255, Centre de Recherches Biomédicales des Cordeliers, 15 rue de l'Ecole de Médecine, 75270 Paris cedex 06, France

¶¶ To whom correspondence should be addressed: Carcinogénèse Hépatique et Virologie Moléculaire, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris cedex 15, France. Tel.: 33-1-45-68-82-61; Fax: 33-1-45-68-87-80; E-mail: abudkow{at}pasteur.fr.

Abstract

We have previously demonstrated that viral particles with the properties of nonenveloped hepatitis C virus (HCV) nucleocapsids occur in the serum of HCV-infected individuals (1). We show here that nucleocapsids purified directly from serum or isolated from HCV virions have FcγR-like activity and bind “nonimmune” IgG via its Fcγ domain. HCV core proteins produced in Escherichia coli and in the baculovirus expression system also bound “nonimmune” IgG and their Fcγ fragments. Folded conformation was required for IgG binding because the FcγR-like site of the core protein was inactive in denaturing conditions. Studies with synthetic core peptides showed that the region spanning amino acids 3–75 was essential for formation of the IgG-binding site. The interaction between the HCV core and human IgG is more efficient in acidic (pH 6.0) than in neutral conditions. The core protein-binding site on the IgG molecule differs from those for C1q, FcγRII (CD32), and FcγRIII (CD16) but overlaps with that for soluble protein A from Staphylococcus aureus (SpA), which is located in the CH2-CH3 interface of IgG. These characteristics of the core-IgG interaction are very similar to those of the neonatal FcRn. Surface plasmon resonance studies suggested that the binding of an anti-core antibody to HCV core protein might be “bipolar” through its paratope to the corresponding epitope and by its Fcγ region to the FcγR-like motif on this protein. These features of HCV nucleocapsids and HCV core protein may confer an advantage for HCV in terms of survival by interfering with host defense mechanisms mediated by the Fcγ part of IgG.

Footnotes

↵1 The abbreviations used are: HCV, hepatitis C virus; HBV, hepatitis B virus; aa, amino acids; HSV, herpes simplex virus; ELISA, enzyme-linked immunosorbent assay; mAb, monoclonal antibody; HRPO, horse-radish peroxidase; PBS, phosphate-buffered saline; BSA, bovine serum albumin; FITC, fluorescein isothiocyanate; SPR, surface plasmon resonance; RU, resonance unit(s).
↵2 Boulant, S., Becchi, M., Penin, F., and Lavergne, J. P. (2003) J. Biol. Chem. 278, 45785–45792.
↵* This work was supported by a grant from Agence Nationale de Recherches sur le SIDA (ANRS) (MK/CP/2002/50). 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.
↵∥ Supported by a Convention Industrielle de Formation par la Recherche (CIFRE) fellowship from the Association Nationale de la Recherche Technique (ANRT) (no. 773/2001) and the Laboratoire Français du Fractionnement et des Biotechnologies (LFB, Les Ulis, France).
↵‡‡ Recipient of a fellowship from Réseau de l'Institut Pasteur.
- Received October 20, 2003.
- Revision received November 7, 2003.
The American Society for Biochemistry and Molecular Biology, Inc.