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Journal of Virology, June 2004, p. 5707-5719, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.5707-5719.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Longitudinal Analysis of CD8+ T Cells Specific for Structural and Nonstructural Hepatitis B Virus Proteins in Patients with Chronic Hepatitis B: Implications for Immunotherapy

George J. M. Webster,1,2 Stephanie Reignat,1 David Brown,2 Graham S. Ogg,3 Louise Jones,3 Suranjith L. Seneviratne,3 Roger Williams,1 Geoffrey Dusheiko,2 and Antonio Bertoletti1,4*

Institute of Hepatology, University College of London, London WC1E 6HX,1 Centre for Hepatology, Royal Free Hospital, London NW3 2QG,2 Molecular Immunology Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom, and INMI "L. Spallanzani," Rome 00149, Italy3

Received 8 October 2003/ Accepted 2 February 2004

The cytotoxic T-cell response in chronic hepatitis B virus (HBV) infection has been described as weak and mono- or oligospecific in comparison to the more robust virus-specific T-cell response present in resolved infection. However, chronic hepatitis B is a heterogeneous disease with markedly variable levels of virus replication and liver disease activity. Here we analyzed (both directly ex vivo and after in vitro stimulation) the HBV-specific CD8 T-cell responses against structural and nonstructural HBV proteins longitudinally in patients with different patterns of chronic infections. We found that the profiles of virus-specific CD8+-T-cell responses during chronic infections are highly heterogeneous and influenced more by the level of HBV replication than by the activity of liver disease. An HBV DNA load of <107 copies/ml appears to be the threshold below which circulating multispecific HBV-specific CD8+ T cells are consistently detected. Furthermore, CD8+ T cells with different specificities are differentially regulated during chronic infections. HBV core-specific CD8+ T cells are associated with viral control, while CD8+ T cells specific for envelope and polymerase epitopes can occasionally be found in the setting of high levels (>107 copies) of HBV replication. These findings have implications for the design of immunotherapy for chronic HBV infections.

* Corresponding author. Mailing address: Institute of Hepatology, University College London, 69-75 Chenies Mews, London WC1E 6HX, United Kingdom. Phone: 44-20-7679 6517. Fax: 44-20-7679 0405. E-mail: a.bertoletti{at}ucl.ac.uk.

Journal of Virology, June 2004, p. 5707-5719, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.5707-5719.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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