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

Peter Wing, Tamara Davenne, Jochen Wettengel, Alvina G Lai, Xiaodong Zhuang, Anindita Chakraborty, Valentina d'Arienzo, Catherine Kramer, Chunkyo Ko, James Harris, Sabrina Schreiner, Martin Higgs, Stephanie Roessler, Joanna Parish, Ulrike Protzer, Peter Balfe, Jan Rehwinkel, Jane A McKeating

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)
151 Downloads (Pure)

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.

Original languageEnglish
JournalLife Science Alliance
Volume2
Issue number2
DOIs
Publication statusPublished - 27 Mar 2019

Bibliographical note

© 2019 Wing et al.

ASJC Scopus subject areas

  • Ecology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Plant Science
  • Health, Toxicology and Mutagenesis

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