Hepatitis B virus-host interactions and novel targets for viral cure

Gaëtan Ligat, Eloi R Verrier, Michael Nassal, Thomas F Baumert, Gaëtan Ligat, Eloi R Verrier, Michael Nassal, Thomas F Baumert

Abstract

Chronic infection with HBV is a major cause of advanced liver disease and hepatocellular carcinoma. Nucleos(t)ide analogues effectively control HBV replication but viral cure is rare. Hence treatment has often to be administered for an indefinite duration, increasing the risk for selection of drug resistant virus variants. PEG-interferon-α-based therapies can sometimes cure infection but suffer from a low response rate and severe side-effects. CHB is characterized by the persistence of a nuclear covalently closed circular DNA (cccDNA), which is not targeted by approved drugs. Targeting host factors which contribute to the viral life cycle provides new opportunities for the development of innovative therapeutic strategies aiming at HBV cure. An improved understanding of the host immune system has resulted in new potentially curative candidate approaches. Here, we review the recent advances in understanding HBV-host interactions and highlight how this knowledge contributes to exploiting host-targeting strategies for a viral cure.

Trial registration: ClinicalTrials.gov NCT04820686.

Conflict of interest statement

Conflict of interest statement

Nothing declared.

Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Figure 1. Host-dependency factors of the HBV…
Figure 1. Host-dependency factors of the HBV life cycle as antiviral targets (adapted from Ref. [4]).
Following binding of the virus to glypican 5 and HSPG, NTCP as high affinity receptor mediated HBV entry into the hepatocytes. Following cell entry, the nucleocapsid transports the rcDNA to the nucleus. There rcDNA is converted into an episomal cccDNA minichromosome that serves as a template for all viral transcripts including pgRNA which is encapsidated and reverse transcribed into new rcDNA. The nucleocapsids can be enveloped and released as virions or be recycled to the nucleus to replenish the cccDNA pool. There remains an unmet need to develop new therapeutic strategies aiming to overcome resistance. Every step of the HBV life cycle is dependent on the host factors, which can be explored as antiviral targets for the development of new therapeutic approaches. Examples for host-targeting strategies: (1) Targeting host-dependency factor of the HBV entry and binding. (2) Silencing of cccDNA transcription by host epigenetic factors. (3) Targeting host factors required in the last steps of the HBV life cycle. (4) Immune modulation. Abbreviations: relaxed circular DNA (rcDNA), covalently closed circular DNA (cccDNA), pregenomic RNA (pgRNA), sodium taurocholate cotransporting polypeptide (NTCP), heparan sulfate proteoGlycan (HSPG).

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Source: PubMed

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