PT  - JOURNAL ARTICLE
AU  - Wing, Peter AC
AU  - Davenne, Tamara
AU  - Wettengel, Jochen
AU  - Lai, Alvina G
AU  - Zhuang, Xiaodong
AU  - Chakraborty, Anindita
AU  - D’Arienzo, Valentina
AU  - Kramer, Catharina
AU  - Ko, Chunkyu
AU  - Harris, James M
AU  - Schreiner, Sabrina
AU  - Higgs, Martin
AU  - Roessler, Stephanie
AU  - Parish, Joanna L
AU  - Protzer, Ulrike
AU  - Balfe, Peter
AU  - Rehwinkel, Jan
AU  - McKeating, Jane A
TI  - A dual role for SAMHD1 in regulating HBV cccDNA and RT-dependent particle genesis
AID  - 10.26508/lsa.201900355
DP  - 2019 Apr 01
TA  - Life Science Alliance
PG  - e201900355
VI  - 2
IP  - 2
4099  - http://www.life-science-alliance.org/content/2/2/e201900355.short
4100  - http://www.life-science-alliance.org/content/2/2/e201900355.full
SO  - Life Sci. Alliance2019 Apr 01; 2
AB  - 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.