Journal
JOURNAL OF HEPATOLOGY
Volume 75, Issue 1, Pages 64-73Publisher
ELSEVIER
DOI: 10.1016/j.jhep.2020.12.034
Keywords
Hepatitis B; hypoxia; HIF; transcription
Categories
Funding
- Wellcome Trust [IA 200838/Z/16/Z]
- MRC [MR/R022011/1]
- Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China [2018-I2M-2-002]
- German research foundation [TRR179, TP14]
- Technical University of Munich via the German Excellence Initiative
- EU 7th Framework Program [291,763]
- Wellcome Trust Senior Clinical Research Fellowship [108070/Z/15/Z]
- Universita del Piemonte Orientale, FAR-2017
- ARC, Paris [TheraHCC2 IHUARC201901299]
- National Institute for Health Research [NIHR-RP-2016-06-004]
- Deanship of Scientific Research, King Abdulaziz University, Ministry of High Education for Saudi Arabia
- European Union [EU H2020-667273-HEPCAR]
- Inserm Plan Cancer
- Institute for Advanced Study
- MRC [MR/R022011/1] Funding Source: UKRI
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HIFs play a crucial role in regulating HBV replication, revealing an evolutionary mechanism by which HBV exploits the HIF signaling pathway to persist in the low oxygen environment of the liver.
Background & Aims: Hypoxia inducible factors (HIFs) are a hallmark of inflammation and are key regulators of hepatic immunity and metabolism, yet their role in HBV replication is poorly defined. HBV replicates in hepatocytes within the liver, a naturally hypoxic organ, however most studies of viral replication are performed under conditions of atmospheric oxygen, where HIFs are inactive. We therefore investigated the role of HIFs in regulating HBV replication. Methods: Using cell culture, animal models, human tissue and pharmacological agents inhibiting the HIF-prolyl hydroxylases, we investigated the impact of hypoxia on the HBV life cycle. Results: Culturing liver cell-based model systems under low oxygen uncovered a new role for HIFs in binding HBV DNA and activating the basal core promoter, leading to increased pregenomic RNA and de novo HBV particle secretion. The presence of hypoxia responsive elements among all primate members of the hepadnaviridae highlights an evolutionary conserved role for HIFs in regulating this virus family. Conclusions: Identifying a role for this conserved oxygen sensor in regulating HBV transcription suggests that this virus has evolved to exploit the HIF signaling pathway to persist in the low oxygen environment of the liver. Our studies show the importance of considering oxygen availability when studying HBV-host interactions and provide innovative routes to better understand and target chronic HBV infection. Lay summary: Viral replication in host cells is defined by the cellular microenvironment and one key factor is local oxygen tension. Hepatitis B virus (HBV) replicates in the liver, a naturally hypoxic organ. Hypoxia inducible factors (HIFs) are the major sensors of low oxygen; herein, we identify a new role for these factors in regulating HBV replication, revealing new therapeutic targets. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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