TY - JOUR T1 - A dual role for SAMHD1 in regulating HBV cccDNA and RT-dependent particle genesis JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201900355 VL - 2 IS - 2 SP - e201900355 AU - Peter AC Wing AU - Tamara Davenne AU - Jochen Wettengel AU - Alvina G Lai AU - Xiaodong Zhuang AU - Anindita Chakraborty AU - Valentina D’Arienzo AU - Catharina Kramer AU - Chunkyu Ko AU - James M Harris AU - Sabrina Schreiner AU - Martin Higgs AU - Stephanie Roessler AU - Joanna L Parish AU - Ulrike Protzer AU - Peter Balfe AU - Jan Rehwinkel AU - Jane A McKeating Y1 - 2019/04/01 UR - https://www.life-science-alliance.org/content/2/2/e201900355.abstract N2 - 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. ER -