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Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: New perspectives for immune therapy

Authors

  • Carolina Boni,

    1. Laboratorio di Immunopatologia Virale, Divisione Malattie Infettive, Azienda Ospedaliera di Parma, and Cattedra di Malattie Infettive, Università di Parma, Italy
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  • Amalia Penna,

    1. Laboratorio di Immunopatologia Virale, Divisione Malattie Infettive, Azienda Ospedaliera di Parma, and Cattedra di Malattie Infettive, Università di Parma, Italy
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  • Graham S. Ogg,

    1. Molecular Immunology Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK
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  • Antonio Bertoletti,

    1. Institute of Hepatology, University College London, London, UK
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  • Massimo Pilli,

    1. Laboratorio di Immunopatologia Virale, Divisione Malattie Infettive, Azienda Ospedaliera di Parma, and Cattedra di Malattie Infettive, Università di Parma, Italy
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  • Cristina Cavallo,

    1. Laboratorio di Immunopatologia Virale, Divisione Malattie Infettive, Azienda Ospedaliera di Parma, and Cattedra di Malattie Infettive, Università di Parma, Italy
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  • Albertina Cavalli,

    1. Laboratorio di Immunopatologia Virale, Divisione Malattie Infettive, Azienda Ospedaliera di Parma, and Cattedra di Malattie Infettive, Università di Parma, Italy
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  • Simona Urbani,

    1. Laboratorio di Immunopatologia Virale, Divisione Malattie Infettive, Azienda Ospedaliera di Parma, and Cattedra di Malattie Infettive, Università di Parma, Italy
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  • Richard Boehme,

    1. GlaxoWellcome, Research Triangle Park, NC
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  • Ruggero Panebianco,

    1. GlaxoWellcome, Verona, Italy
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  • Franco Fiaccadori,

    1. Laboratorio di Immunopatologia Virale, Divisione Malattie Infettive, Azienda Ospedaliera di Parma, and Cattedra di Malattie Infettive, Università di Parma, Italy
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  • Carlo Ferrari r1">Address reprint requests to: Carlo Ferrari M.D.

    Corresponding author
    1. Laboratorio di Immunopatologia Virale, Divisione Malattie Infettive, Azienda Ospedaliera di Parma, and Cattedra di Malattie Infettive, Università di Parma, Italy
    • Laboratorio di Immunopatologia Virale, Divisione Malattie Infettive, Azienda Ospedaliera di Parma, via Gramsci 14,43100 Parma, Italy. E-mail: cafer@tin.it; fax: (39) 521-988706.
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Abstract

The hepatitis B virus (HBV) cytotoxic T lymphocyte (CTL) response in patients with chronic HBV infection is generally weak or totally undetectable. This inability to mount protective CTL responses is believed to be a crucial determinant of viral persistence, and its correction represents an important objective of immune therapies for chronic hepatitis B. However, amplification of CTL responses in vivo may be ineffective if HBV-specific CD8 cells are either absent or nonresponsive to exogenous stimulation. In this study, we asked whether antiviral treatments able to inhibit viral replication and to reduce viral and antigen load can successfully reconstitute CTL responses creating the appropriate conditions for their therapeutic stimulation. For this purpose, the HBV-specific CTL response before and during lamivudine therapy was studied longitudinally in 6 HLA-A2–positive patients with HBeAg+ chronic hepatitis B. Both HBV-specific cytotoxic T cell activity measured by chromium release assay on peptide stimulation in vitro and CD8+ T cell frequency measured ex vivo by HLA-A2/peptide tetramer staining were significantly augmented by lamivudine therapy. This enhancement followed the reconstitution of CD4 reactivity and the decline of viral load induced by therapy. Our study shows that lamivudine treatment in chronic hepatitis B can restore CTL reactivity, making CTL susceptible to exogenous stimulation. This effect may enhance the probability that T cell-based immune therapies delivered after lamivudine treatment can successfully reconstitute a protective CTL response able to cure chronic HBV infection. (HEPATOLOGY 2001;33:963-971.)

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