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Wing, P.A.* ; Liu, P.J.* ; Harris, J.M.* ; Magri, A.* ; Michler, T. ; Zhuang, X.* ; Borrmann, H.* ; Minisini, R.* ; Frampton, N.R.* ; Wettengel, J.M. ; Mailly, L.* ; D'Arienzo, V.* ; Riedl, T.* ; Nobre, L.* ; Weekes, M.P.* ; Pirisi, M.* ; Heikenwalder, M.* ; Baumert, T.F.* ; Hammond, E.M.* ; Mole, D.R.* ; Protzer, U. ; Balfe, P.* ; McKeating, J.A.*

Hypoxia inducible factors regulate hepatitis B virus replication by activating the basal core promoter.

J. Hepatol. 75, 64-73 (2021)
Verlagsversion DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
BACKGROUND AND AIMS: Chronic hepatitis B virus (HBV) infection is a major cause of liver disease and hepatocellular carcinoma. Hypoxia inducible factors (HIFs) are a hallmark of inflammation and are key regulators of hepatic immunity and metabolism and 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 pre-genomic RNA and de novo HBV particle secretion. The presence of hypoxia responsive elements among all primate members of the hepadnaviridae highlight 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-signalling 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 understanding and therapeutic targeting of chronic HBV infection.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Hif ; Hepatitis B ; Hypoxia ; Transcription; Liver; Transcription; Dna; Hepatocytes; Mechanisms; Estrogen; Sequence; Disease; Anemia; Level
ISSN (print) / ISBN 0168-8278
e-ISSN 1600-0641
Zeitschrift Journal of Hepatology
Quellenangaben Band: 75, Heft: 1, Seiten: 64-73 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort Radarweg 29, 1043 Nx Amsterdam, Netherlands
Begutachtungsstatus Peer reviewed
Förderungen Universita del Piemonte Orientale, FAR-2017
Wellcome Trust Senior Clinical Research Fellowship
EU 7th Framework Program
Technical University of Munich via the German Excellence Initiative
German Research Foundation
Institute for Advanced Study
Inserm Plan Cancer
European Union
Deanship of Scientific Research, King Abdulaziz University, Ministry of High Education for Saudi Arabia
National Institute for Health Research
MRC
Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China
Wellcome Trust
ARC, Paris