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Journal of Virology, March 2005, p. 3016-3027, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.3016-3027.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Immune Tolerance Split between Hepatitis B Virus Precore and Core Proteins

Margaret Chen,1,2 Matti Sällberg,2,3 Janice Hughes,2 Joyce Jones,2 Luca G. Guidotti,4 Francis V. Chisari,4 Jean-Noel Billaud,2 and David R. Milich2*

Karolinska Institute and Swedish Institute for Infectious Disease Control,1 Division of Clinical Virology, Karolinska Institute at Karolinska University Hospital, Huddinge, Stockholm, Sweden,3 Vaccine Research Institute of San Diego, San Diego,2 Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California4

Received 4 August 2004/ Accepted 12 October 2004

The function of the hepatitis B virus (HBV) precore or HBeAg is largely unknown because it is not required for viral assembly, infection, or replication. However, the HBeAg does appear to play a role in viral persistence. It has been suggested that the HBeAg may promote HBV chronicity by functioning as an immunoregulatory protein. As a model of chronic HBeAg exposure and to examine the tolerogenic potential of the HBV precore and core (HBcAg) proteins, HBc/HBeAg-transgenic (Tg) mice crossed with T cell receptor (TCR)-Tg mice expressing receptors for the HBc/HBeAgs (i.e., TCR-antigen double-Tg pairs) were produced. This study revealed three phenotypes of HBe/HBcAg-specific T-cell tolerance: (i) profound T-cell tolerance most likely mediated by clonal deletion, (ii) T-cell clonal ignorance, and (iii) nondeletional T-cell tolerance mediated by clonal anergy and dependent on the structure, location, and concentration of the tolerogen. The secreted HBeAg is significantly more efficient than the intracellular HBcAg at eliciting T-cell tolerance. The split T-cell tolerance between the HBeAg and the HBcAg and the clonal heterogeneity of HBc/HBeAg-specific T-cell tolerance may have significant implications for natural HBV infection and especially for precore-negative chronic hepatitis.

* Corresponding author. Mailing address: Vaccine Research Institute of San Diego, 3030 Bunker Hill St., Suite 300, San Diego, CA 92109. Phone: (858) 581-3960, ext. 226. Fax: (858) 581-3970. E-mail: dmilich{at}vrisd.org.

Journal of Virology, March 2005, p. 3016-3027, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.3016-3027.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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