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Journal of Virology, March 2004, p. 2994-3002, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.2994-3002.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Characterization of Functional Hepatitis C Virus Envelope Glycoproteins

Anne Op De Beeck,1,{dagger} Cécile Voisset,1,{dagger} Birke Bartosch,2 Yann Ciczora,1 Laurence Cocquerel,1 Zhenyong Keck,3 Steven Foung,3 François-Loïc Cosset,2 and Jean Dubuisson1*

CNRS-UPR2511, Institut de Biologie de Lille and Institut Pasteur de Lille, Lille,1 Laboratoire de Vectorologie Rétrovirale et Thérapie Génique, INSERM U412, IFR 74, Ecole Normale Supérieure de Lyon, Lyon, France,2 Department of Pathology, Stanford University, Stanford, California3

Received 29 August 2003/ Accepted 1 December 2003

Hepatitis C virus (HCV) encodes two envelope glycoproteins, E1 and E2, that assemble as a noncovalent heterodimer which is mainly retained in the endoplasmic reticulum. Because assembly into particles and secretion from the cell lead to structural changes in viral envelope proteins, characterization of the proteins associated with the virion is necessary in order to better understand how they mature to be functional in virus entry. There is currently no efficient and reliable cell culture system to amplify HCV, and the envelope glycoproteins associated with the virion have therefore not been characterized yet. Recently, infectious pseudotype particles that are assembled by displaying unmodified HCV envelope glycoproteins on retroviral core particles have been successfully generated. Because HCV pseudotype particles contain fully functional envelope glycoproteins, these envelope proteins, or at least a fraction of them, should be in a mature conformation similar to that on the native HCV particles. In this study, we used conformation-dependent monoclonal antibodies to characterize the envelope glycoproteins associated with HCV pseudotype particles. We showed that the functional unit is a noncovalent E1E2 heterodimer containing complex or hybrid type glycans. We did not observe any evidence of maturation by a cellular endoprotease during the transport of these envelope glycoproteins through the secretory pathway. These envelope glycoproteins were recognized by a panel of conformation-dependent monoclonal antibodies as well as by CD81, a molecule involved in HCV entry. The functional envelope glycoproteins associated with HCV pseudotype particles were also shown to be sensitive to low-pH treatment. Such conformational changes are likely necessary to initiate fusion.

* Corresponding author. Mailing address: Unité Hépatite C, CNRS-UPR2511, Institut de Biologie de Lille, 1 rue Calmette, BP 447, 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.

{dagger} A.O.D.B. and C.V. contributed equally to the results of this study.

Journal of Virology, March 2004, p. 2994-3002, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.2994-3002.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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