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Journal of Virology, April 2007, p. 4215-4225, Vol. 81, No. 8
0022-538X/07/$08.00+0     doi:10.1128/JVI.02844-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Characterization of Hepatitis B Virus (HBV)-Specific T-Cell Dysfunction in Chronic HBV Infection

Carolina Boni,^1, Paola Fisicaro,^1, Caterina Valdatta,¹ Barbara Amadei,¹ Paola Di Vincenzo,¹ Tiziana Giuberti,¹ Diletta Laccabue,¹ Alessandro Zerbini,¹ Albertina Cavalli,¹ Gabriele Missale,¹ Antonio Bertoletti,² and Carlo Ferrari^1*

Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy,¹ Centre of Molecular Medicine, Agency for Science, Technology and Research, Singapore²

Received 22 December 2006/ Accepted 30 January 2007

Dysfunctional CD8⁺ T cells present in chronic virus infections can express programmed death 1 (PD-1) molecules, and the inhibition of the engagement of PD-1 with its ligand (PD-L1) has been reported to enhance the antiviral function of these T cells. We took advantage of the wide fluctuations in levels of viremia which are typical of chronic hepatitis B virus (HBV) infection to comprehensively analyze the impact of prolonged exposure to different virus quantities on virus-specific T-cell dysfunction and on its reversibility through the blocking of the PD-1/PD-L1 pathway. We confirm that chronic HBV infection has a profound effect on the HBV-specific T-cell repertoire. Despite the use of a comprehensive panel of peptides covering all HBV proteins, HBV-specific T cells were rarely observed directly ex vivo in samples from patients with chronic infection, in contrast to those from patients with acute HBV infection. In chronic HBV infection, virus-specific T cells were detected mainly in patients with lower levels of viremia. These HBV-specific CD8⁺ T cells expressed PD-1, and their function was improved by the blocking of PD-1/PD-L1 engagement. Thus, a broad spectrum of anti-HBV immunity is expressed by patients with chronic HBV infection and this spectrum is proportional to HBV replication levels and can be improved by blocking the PD-1/PD-L1 pathway. This information may be useful for the design of immunotherapeutic strategies to complement and optimize available antiviral therapies.

Published ahead of print on 7 February 2007.

C. Boni and P. Fisicaro contributed equally to this work.

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