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      New Viral and Immunological Targets for Hepatitis B Treatment and Cure: A Review

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          Abstract

          Although current therapies can be successful at suppressing hepatitis B viral load, long-term viral cure is not within reach. Subsequent strategies combining pegylated interferon alfa with nucleoside/nucleotide analogues have not resulted in any major paradigm shift. An improved understanding of the hepatitis B virus (HBV) lifec ycle and virus-induced immune dysregulation has, however, revealed many potential therapeutic targets, and there are hopes that treatment of hepatitis B could soon be revolutionized. This review summarizes the current developments in HBV therapeutics—both virus directed and host directed.

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          The blockade of immune checkpoints in cancer immunotherapy.

          Drew M Pardoll (2012)
          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus

            Huan Yan, Guocai Zhong, Guangwei Xu … (2012)
            Human hepatitis B virus (HBV) infection and HBV-related diseases remain a major public health problem. Individuals coinfected with its satellite hepatitis D virus (HDV) have more severe disease. Cellular entry of both viruses is mediated by HBV envelope proteins. The pre-S1 domain of the large envelope protein is a key determinant for receptor(s) binding. However, the identity of the receptor(s) is unknown. Here, by using near zero distance photo-cross-linking and tandem affinity purification, we revealed that the receptor-binding region of pre-S1 specifically interacts with sodium taurocholate cotransporting polypeptide (NTCP), a multiple transmembrane transporter predominantly expressed in the liver. Silencing NTCP inhibited HBV and HDV infection, while exogenous NTCP expression rendered nonsusceptible hepatocarcinoma cells susceptible to these viral infections. Moreover, replacing amino acids 157–165 of nonfunctional monkey NTCP with the human counterpart conferred its ability in supporting both viral infections. Our results demonstrate that NTCP is a functional receptor for HBV and HDV. DOI: http://dx.doi.org/10.7554/eLife.00049.001
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              Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection.

              Carolina Boni, Paola Fisicaro, Caterina Valdatta … (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.
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                Author and article information

                Contributors
                Joop E. Arends: j.e.arends@umcutrecht.nl
                Journal
                Journal ID (nlm-ta): Infect Dis Ther
                Journal ID (iso-abbrev): Infect Dis Ther
                Title: Infectious Diseases and Therapy
                Publisher: Springer Healthcare (Cheshire )
                ISSN (Print): 2193-8229
                ISSN (Electronic): 2193-6382
                Publication date (Electronic): 25 October 2017
                Publication date PMC-release: 25 October 2017
                Publication date (Print): December 2017
                Volume: 6
                Issue: 4
                Pages: 461-476
                Affiliations
                [1 ]ISNI 0000000090126352, GRID grid.7692.a, Department of Internal Medicine, Section Infectious Diseases, , University Medical Center Utrecht, ; Utrecht, The Netherlands
                [2 ]ISNI 0000000120346234, GRID grid.5477.1, Utrecht University, ; Utrecht, The Netherlands
                [3 ]ISNI 0000 0004 0400 7971, GRID grid.416450.2, Regional Infectious Diseases Unit, , North Manchester General Hospital, ; Manchester, UK
                Article
                Publisher ID: 173
                DOI: 10.1007/s40121-017-0173-y
                PMC ID: 5700893
                PubMed ID: 29071665
                SO-VID: d315c90f-763a-4636-b6b3-82ad2131dd67
                Copyright © © The Author(s) 2017
                History
                Date received : 22 August 2017
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © Springer Healthcare Ltd., part of Springer Nature 2017

                Keywords: antiviral therapy,hepatitis b virus,immunomodulators,nonnucleoside antivirals,nucleoside analogues
                Data availability:
                Keywords: antiviral therapy, hepatitis b virus, immunomodulators, nonnucleoside antivirals, nucleoside analogues

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