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Restoring, releasing or replacing adaptive immunity in chronic hepatitis B

Nature Reviews Gastroenterology & Hepatology volume 16, pages 662–675 (2019)Cite this article

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Abstract

Multiple new therapeutic approaches are currently being developed to achieve sustained, off-treatment suppression of HBV, a persistent hepatotropic infection that kills ~2,000 people a day. A fundamental therapeutic goal is the restoration of robust HBV-specific adaptive immune responses that are able to maintain prolonged immunosurveillance of residual infection. Here, we provide insight into key components of successful T cell and B cell responses to HBV, discussing the importance of different specificities and effector functions, local intrahepatic immunity and pathogenic potential. We focus on the parallels and interactions between T cell and B cell responses, highlighting emerging areas for future investigation. We review the potential for different immunotherapies in development to restore or release endogenous adaptive immunity by direct or indirect approaches, including limitations and risks. Finally, we consider an alternative HBV treatment strategy of replacing failed endogenous immunity with infusions of highly targeted T cells or antibodies.

Key points

  • Unprecedented opportunities exist to develop immunotherapeutic approaches that complement novel antiviral agents to achieve sustained control of residual HBV in chronic HBV infection (CHB).

  • Adaptive immune responses (HBV-specific T cells and B cells) provide precise antiviral targeting of HBV-infected hepatocytes and/or virions, but also have the potential to trigger tissue damage.

  • HBV-specific T cell and B cell responses should be examined in parallel to consider their crosstalk, complementary effector mechanisms and their features of dysfunction in CHB.

  • Inadequate HBV-specific T cell and B cell responses might be restored by immunogenic therapeutic vaccines and might be released from inhibition by antigen load reduction or more specific immunomodulation such as checkpoint inhibition.

  • Alternatively, the failed endogenous adaptive response can be replaced with targeted exogenous T cell- or B cell-derived HBV-specific effectors.

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Fig. 1: Antiviral functions of HBV-specific CD8+ T cells.
Fig. 2: Antiviral functions of B cells and antibodies in HBV infection.
Fig. 3: Interactions between B cells and CD4+ T cells.
Fig. 4: Modulation of adaptive immunity by immunotherapeutic approaches.

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Acknowledgements

M.K.M.’s laboratory is supported by funding from the Wellcome Trust, Cancer Research UK, Medical Research Foundation and the National Institute for Health Research. A.R.B. was funded by a F. Hoffmann-La Roche–University College London joint Impact Studentship.

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    Mala K. Maini & Alice R. Burton

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M.K.M. receives collaborative research funding from Gilead Sciences and Immunocore and has served as a consultant or on advisory boards for Arbutus Biopharma, F. Hoffmann-La Roche, Gilead Sciences, Immunocore and Janssen.

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Maini, M.K., Burton, A.R. Restoring, releasing or replacing adaptive immunity in chronic hepatitis B. Nat Rev Gastroenterol Hepatol 16, 662–675 (2019). https://doi.org/10.1038/s41575-019-0196-9

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