A dual role for SAMHD1 in regulating HBV cccDNA and RT-dependent particle genesis
Wing PAC., Davenne T., Wettengel J., Lai AG., Zhuang X., Chakraborty A., D’Arienzo V., Kramer C., Ko C., Harris JM., Schreiner S., Higgs M., Roessler S., Parish JL., Protzer U., Balfe P., Rehwinkel J., McKeating JA.
<jats:p>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 <jats:italic>Samhd1</jats:italic> 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.</jats:p>