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Journal of Virology, November 2005, p. 13199-13208, Vol. 79, No. 21
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.21.13199-13208.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Analysis of a Highly Flexible Conformational Immunogenic Domain A in Hepatitis C Virus E2

Zhen-Yong Keck,1 Ta-Kai Li,1 Jinming Xia,1 Birke Bartosch,2 François-Loïc Cosset,2 Jean Dubuisson,3 and Steven K. H. Foung1*

Department of Pathology, Stanford University School of Medicine, Stanford, California 94305,1 Laboratoire de Vectorologie Rétrovirale et Thérapie Génique, INSERM U412, IFR 74, Ecole Normale Supérieure de Lyon, Lyon, France,2 CNRS-UPR2511, Institut de Biologie de Lille, and Institut Pasteur de Lille, Lille, France3

Received 18 May 2005/ Accepted 8 August 2005

Hepatitis C (HCV) E2 glycoprotein is involved in virus attachment and entry, and its structural organization is largely unknown. Characterization of a panel of human monoclonal antibodies (HMAbs) to HCV by competition studies has led to an immunogenic organization model of E2 with three domains designated A, B, and C and epitopes in each domain having similar structural and functional properties. Domain A contains nonneutralizing epitopes, and domains B and C contain neutralizing epitopes. The isolation and characterization of three new HMAbs within domain A for a total of six provide support for this model. All six domain A HMAbs do not neutralize HCV retroviral pseudotype particle (HCVpp) infection on Huh-7 cells, and all six HMAbs have similar binding affinity and maximum binding, Bmax, a relative indicator of epitope density, as other neutralizing HMAbs, suggesting that neutralization is epitope specific and not by binding to any surface epitope. The dose-dependent neutralizing activity of CBH-7, an HMAb to a domain C epitope in spatial proximity to domain A, and of CBH-5, a domain B HMAb to a more distant epitope, were tested in the presence and absence of each domain A HMAb. No enhancement or reduction in CBH-7 or CBH-5 neutralizing activity was observed, indicating that the potential induction of nonneutralizing antibodies should not be a central issue for HCV vaccine design. To assess whether domain A is involved in the structural changes as part of a pH-dependent virus envelope fusion process, changes in antibody binding patterns to normal pH and acid pH-treated HCVpp were measured. Antibody binding affinity of HMAbs to HCVpp was not affected by low pH. However, the Bmax values for low-pH-treated HCVpp with antibodies to domain A increased 46%, for domain C (CBH-7) they increased 23%, and for domain B (CBH-5) there was a decrease of 12%. Collectively, the organization and function of HCV E2 antigenic domains are roughly analogous to the large envelope glycoprotein E organizational structure for other flaviviruses with three distinct structural and functional domains.

* Corresponding author. Mailing address: Stanford Medical School Blood Center, 3373 Hillview Ave., Palo Alto, CA 94304. Phone: (650) 723-6481. Fax: (650) 725-6610. E-mail: sfoung{at}stanford.edu.

Journal of Virology, November 2005, p. 13199-13208, Vol. 79, No. 21
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.21.13199-13208.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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