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Journal of Virology, July 2001, p. 6367-6374, Vol. 75, No. 14
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.14.6367-6374.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Molecular Basis for the Interaction of the Hepatitis B Virus Core Antigen with the Surface Immunoglobulin Receptor on Naive B Cells

Una Lazdina,1,2 Tinghua Cao,3 Juris Steinbergs,1,2 Mats Alheim,1 Paul Pumpens,2 Darrel L. Peterson,4 David R. Milich,5 Geert Leroux-Roels,3 and Matti Sällberg1,*

Divisions of Clinical Virology, F 68, and Biomedical Laboratory Technology, Karolinska Institutet at Huddinge University Hospital, S-141 86 Huddinge, Sweden1; Biomedical Research and Study Centre, University of Latvia, LV 1067 Riga, Latvia2; Center for Vaccinology, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium3; Department of Biochemistry and Molecular Biophysics, Virginia Commonwealth University, Richmond, Virginia4; and Vaccine Research Institute of San Diego, San Diego, California5

Received 20 December 2000/Accepted 25 April 2001

The nucleocapsid of the hepatitis B virus (HBV) is composed of 180 to 240 copies of the HBV core (HBc) protein. HBc antigen (HBcAg) capsids are extremely immunogenic and can activate naive B cells by cross-linking their surface receptors. The molecular basis for the interaction between HBcAg and naive B cells is not known. The functionality of this activation was evidenced in that low concentrations of HBcAg, but not the nonparticulate homologue HBV envelope antigen (HBeAg), could prime naive B cells to produce anti-HBc in vitro with splenocytes from HBcAg- and HBeAg-specific T-cell receptor transgenic mice. The frequency of these HBcAg-binding B cells was estimated by both hybridoma techniques and flow cytometry (B7-2 induction and direct HBcAg binding) to be approximately 4 to 8% of the B cells in a naive spleen. Cloning and sequence analysis of the immunoglobulin heavy- and light-chain variable (VH and VL) domains of seven primary HBcAg-binding hybridomas revealed that six (86%) were related to the murine and human VH1 germ line gene families and one was related to the murine VH3 family. By using synthetic peptides spanning three VH1 sequences, one VH3 sequence, and one VLkappa V sequence, a linear motif in the framework region 1 (FR1)complementarity-determining region 1 (CDR1) junction of the VH1 sequence was identified that bound HBcAg. Interestingly, the HBcAg-binding motif was present in the VL domain of the HBcAg-binding VH3-encoded antibody. Finally, two monoclonal antibodies containing linear HBcAg-binding motifs blocked HBcAg presentation by purified naive B cells to purified HBcAg-primed CD4+ T cells. Thus, the ability of HBcAg to bind and activate a high frequency of naive B cells seems to be mediated through a linear motif present in the FR1-CDR1 junction of the heavy or light chain of the B-cell surface receptor.

* Corresponding author. Mailing address: Division of Clinical Virology, F 68, Huddinge University Hospital, S-141 86 Huddinge, Sweden. Phone: 46-8-5858 7939. Fax: 46-8-5858 7933. E-mail: misg{at}labd01.hs.sll.se.

Journal of Virology, July 2001, p. 6367-6374, Vol. 75, No. 14
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.14.6367-6374.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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