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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA, Circular / genetics*
  • DNA, Viral / genetics
  • Gene Knockout Techniques
  • Hep G2 Cells
  • Hepatitis B virus / genetics*
  • Hepatitis B, Chronic / enzymology
  • Hepatitis B, Chronic / virology
  • Humans
  • RNA-Directed DNA Polymerase / genetics*
  • Reverse Transcription / genetics
  • SAM Domain and HD Domain-Containing Protein 1 / genetics*
  • Transcriptional Activation
  • Transfection
  • Virus Replication / genetics


  • DNA, Circular
  • DNA, Viral
  • RNA-Directed DNA Polymerase
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human