Hepatitis B virus as a gene delivery vector activating foreign antigenic T cell response that abrogates viral expression in mouse models

Authors

  • Qiang Deng,

    1. Laboratoire Pathogenèse des Virus de l'Hépatite B, Institut Pasteur, Paris, France
    2. Institut National de la Santé et de la Recherche Médicale U845, Centre de Recherche Croissance et Signalisation, Faculté de Médecine Paris Descartes, Paris, France
    Current affiliation:
    1. Unit of Tumor Virus, Institut Pasteur of Shanghai, Shanghai, China
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  • Maryline Mancini-Bourgine,

    1. Laboratoire Pathogenèse des Virus de l'Hépatite B, Institut Pasteur, Paris, France
    2. Institut National de la Santé et de la Recherche Médicale U845, Centre de Recherche Croissance et Signalisation, Faculté de Médecine Paris Descartes, Paris, France
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  • Xiaoming Zhang,

    1. Unité Régulation Immunitaire et Vaccinologie, Paris, France
    2. Institut National de la Santé et de la Recherche Médicale U883, Paris, France
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  • Marie-Christine Cumont,

    1. Unité de Recherche et d'Expertise Histotechnologie et Pathologie, Institut Pasteur, Paris, France
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  • Ren Zhu,

    1. Laboratoire Pathogenèse des Virus de l'Hépatite B, Institut Pasteur, Paris, France
    2. Institut National de la Santé et de la Recherche Médicale U845, Centre de Recherche Croissance et Signalisation, Faculté de Médecine Paris Descartes, Paris, France
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  • Yu-Chun Lone,

    1. Institut National de la Santé et de la Recherche Médicale U542, Hôpital Paul Brousse, Villejuif, France
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  • Marie-Louise Michel

    Corresponding author
    1. Laboratoire Pathogenèse des Virus de l'Hépatite B, Institut Pasteur, Paris, France
    2. Institut National de la Santé et de la Recherche Médicale U845, Centre de Recherche Croissance et Signalisation, Faculté de Médecine Paris Descartes, Paris, France
    • Bâtiment Lwoff, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris Cedex 15
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    • fax: (33)-1-40-61-38-41.


  • Potential conflict of interest: Nothing to report.

Abstract

Chronic hepatitis B virus (HBV) infection is characterized by functionally impaired T cell responses. To ensure active immunotherapy, the immune response must be switched from exhausted T cells to functional effectors that can attain the liver and cure the viral infection. We thus designed a recombinant HBV (rHBV) containing a modified viral core gene that specifically delivers a foreign antigenic polyepitope to the liver. This recombinant virus could only be self-maintained in hepatocytes already infected by HBV through capsid complementation. A strong foreign epitope-specific T cell response was first primed in the periphery by way of DNA immunization in human leukocyte antigen (HLA)-A2/DR1 transgenic mice. After the hydrodynamic (hyd.) injection of rHBV, expression of the foreign antigenic polyepitope in hepatocytes attracted/reactivated a vigorous T cell response in situ. Most liver-infiltrating CD8+ T cells proved to be functional effectors. Following DNA priming and hyd. injection, the rHBV-based expression of hepatitis B surface antigen (HBsAg) in mouse liver was almost completely inhibited without causing major liver injury. Studies in HBsAg/HLA-A2/DR1 transgenic mice further validated our approach. Conclusion: For the first time, HBV was used as a gene delivery vector, which strongly triggered functional T cell response and subsequently controlled the viral expression in the liver of surrogate mouse models for HBV infection. It might represent an innovative and promising strategy of active immunotherapy during HBV persistent infection. This concept could even be more generally extended to other chronic viral diseases. (HEPATOLOGY 2009.)

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