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Life Sci Alliance. 2019 Mar 27;2(2). pii: e201900355. doi: 10.26508/lsa.201900355. Print 2019 Apr.

A dual role for SAMHD1 in regulating HBV cccDNA and RT-dependent particle genesis.

Author information

1
Nuffield Department of Medicine, University of Oxford, Oxford, UK.
2
Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
3
Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.
4
German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany.
5
Institutes of Cancer and Genomic Sciences and Immunity and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, UK.
6
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
7
Nuffield Department of Medicine, University of Oxford, Oxford, UK jane.mckeating@ndm.ox.ac.uk.

Abstract

Chronic hepatitis B is one of the world's unconquered diseases with more than 240 million infected subjects at risk of developing liver disease and hepatocellular carcinoma. Hepatitis B virus reverse transcribes pre-genomic RNA to relaxed circular DNA (rcDNA) that comprises the infectious particle. To establish infection of a naïve target cell, the newly imported rcDNA is repaired by host enzymes to generate covalently closed circular DNA (cccDNA), which forms the transcriptional template for viral replication. SAMHD1 is a component of the innate immune system that regulates deoxyribonucleoside triphosphate levels required for host and viral DNA synthesis. Here, we show a positive role for SAMHD1 in regulating cccDNA formation, where KO of SAMHD1 significantly reduces cccDNA levels that was reversed by expressing wild-type but not a mutated SAMHD1 lacking the nuclear localization signal. The limited pool of cccDNA in infected Samhd1 KO cells is transcriptionally active, and we observed a 10-fold increase in newly synthesized rcDNA-containing particles, demonstrating a dual role for SAMHD1 to both facilitate cccDNA genesis and to restrict reverse transcriptase-dependent particle genesis.

PMID:
30918010
PMCID:
PMC6438393
DOI:
10.26508/lsa.201900355
[Indexed for MEDLINE]
Free PMC Article

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