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Journal of Virology, August 2007, p. 8101-8111, Vol. 81, No. 15
0022-538X/07/$08.00+0     doi:10.1128/JVI.00127-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Neutralizing Activity of Anti-Hepatitis C Virus Antibodies Is Modulated by Specific Glycans on the E2 Envelope Protein{triangledown}

François Helle,1,{dagger} Anne Goffard,1,2,{dagger} Virginie Morel,1,3 Gilles Duverlie,1,3 Jane McKeating,4 Zhen-Yong Keck,5 Steven Foung,5 François Penin,6 Jean Dubuisson,1* and Cécile Voisset1

Institut de Biologie de Lille (UMR8161), CNRS, Université Lille I & II and Institut Pasteur de Lille, Lille, France,1 Service de Virologie/UPRES EA3610, Faculté de Médecine, Université Lille II, Lille, France,2 Laboratoire de Virologie, Centre Hospitalier Universitaire d'Amiens, Amiens, France,3 Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom,4 Department of Pathology, Stanford University School of Medicine, Stanford, California,5 Institut de Biologie et Chimie des Protéines, UMR5086, CNRS, Université de Lyon, IFR128 BioSciences Lyon-Gerland, 69367 Lyon, France6

Received 19 January 2007/ Accepted 13 May 2007

Hepatitis C virus (HCV) envelope glycoproteins are highly glycosylated, with up to 5 and 11 N-linked glycans on E1 and E2, respectively. Most of the glycosylation sites on HCV envelope glycoproteins are conserved, and some of the glycans associated with these proteins have been shown to play an essential role in protein folding and HCV entry. Such a high level of glycosylation suggests that these glycans can limit the immunogenicity of HCV envelope proteins and restrict the binding of some antibodies to their epitopes. Here, we investigated whether these glycans can modulate the neutralizing activity of anti-HCV antibodies. HCV pseudoparticles (HCVpp) bearing wild-type glycoproteins or mutants at individual glycosylation sites were evaluated for their sensitivity to neutralization by antibodies from the sera of infected patients and anti-E2 monoclonal antibodies. While we did not find any evidence that N-linked glycans of E1 contribute to the masking of neutralizing epitopes, our data demonstrate that at least three glycans on E2 (denoted E2N1, E2N6, and E2N11) reduce the sensitivity of HCVpp to antibody neutralization. Importantly, these three glycans also reduced the access of CD81 to its E2 binding site, as shown by using a soluble form of the extracellular loop of CD81 in inhibition of entry. These data suggest that glycans E2N1, E2N6, and E2N11 are close to the binding site of CD81 and modulate both CD81 and neutralizing antibody binding to E2. In conclusion, this work indicates that HCV glycans contribute to the evasion of HCV from the humoral immune response.

* Corresponding author. Mailing address: Hepatitis C Laboratory, CNRS-UMR8161, Institut de Biologie de Lille, 1 rue Calmette, BP447, 59021 Lille cedex, France. Phone: (33) 3 20 87 11 60. Fax: (33) 3 20 87 12 01. E-mail: jean.dubuisson{at}ibl.fr

{triangledown} Published ahead of print on 23 May 2007.

{dagger} F.H. and A.G. contributed equally to this work.

Journal of Virology, August 2007, p. 8101-8111, Vol. 81, No. 15
0022-538X/07/$08.00+0     doi:10.1128/JVI.00127-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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