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.