Inhibition of Hepatitis B virus replication by SAMHD1

•SAMHD1 expression is detectable in four liver cell lines.•SAMHD1 inhibits HBV replication in SMMC-7721 and BEL-7402 cells.•SAMHD1 HD/AA with no dNTPase activity blocks HBV replication in liver cells.•HBV replication reduces SAMHD1 expression in HepG2 cells.•IFN-α induces SAMHD1 expression in liver cells. Sterile alpha motif and HD-domain containing protein 1 (SAMHD1) is a newly identified intracellular antiviral factor. By depleting the dNTPs pool of host cells to a low level that cannot support the efficient synthesis of viral cDNA, it restricts replication of some retroviruses. As a DNA virus, Hepatitis B virus (HBV) experiences a process of reverse transcription in its life cycle akin to that of retroviruses. However, whether SAMHD1 can restrict HBV replication in liver cells is unknown. Here, we reported that SAMHD1 expression was detectable in four liver cell lines. Exogenous expression of SAMHD1 in SMMC-7721 cells restrained HBV replication. Similarly, SAMHD1 impeded HBV replication in another liver cell line, BEL-7402. Remarkably, the catalytically inactive mutant, SAMHD1 HD/AA also hampered HBV replication. Additionally, HBV replication reduced SAMHD1 expression in HepG2 cells. Moreover, it was found that IFN-α induced expression of SAMHD1 in liver cells. Together, these findings suggested that IFN-α-inducible SAMHD1 inhibited HBV replication in liver cells.