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

Research output: Contribution to journalArticle

Authors

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

External organisations

  • Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
  • Medical Research Council (MRC) Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
  • Tech Univ Munich
  • Nuffield Department of Medicine, University of Oxford, Oxford, Oxfordshire, OX3 7AZ, UK.
  • 4 Nuffield Department of Medicine, University of Oxford, Oxford, 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.

Bibliographic note

© 2019 Wing et al.

Details

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