Abstract
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.
Highlights
Chronic hepatitis B is one of the world’s most economically important diseases, with 2 billion people exposed to the virus at some stage of their lives
Our study highlights a dual role for SAMHD1 in the Hepatitis B virus (HBV) life cycle, a positive role in regulating closed circular DNA (cccDNA) levels and a restriction of polymerase-mediated reverse transcription of pgRNA to relaxed circular DNA (rcDNA)
Since our experiments focus on the first 3 d of infection and cccDNA is long-lived with an estimated half-life of 40 d in vitro (Ko et al, 2018), we are unable to assess the role of SAMHD1 in cccDNA maintenance
Summary
Chronic hepatitis B is one of the world’s most economically important diseases, with 2 billion people exposed to the virus at some stage of their lives. The rcDNA is imported to the nucleus and converted to covalently closed circular DNA (cccDNA) that serves as the transcriptional template for viral RNAs. The rcDNA represents the mature form of the viral genome that is packaged into nucleocapsids that are enveloped and released as newly formed infectious virions or redirected toward the nucleus to replenish and maintain the pool of episomal cccDNA. The rcDNA represents the mature form of the viral genome that is packaged into nucleocapsids that are enveloped and released as newly formed infectious virions or redirected toward the nucleus to replenish and maintain the pool of episomal cccDNA This amplification pathway, together with the long half-life of cccDNA contributes to viral persistence (Urban et al, 2010; Ko et al, 2018). HBV does not require integration into the host genome for replication; integrated viral DNA fragments are commonly found in chronic hepatitis B and may contribute to carcinogenesis (Tu & Urban, 2018)
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