Activities of endogenous APOBEC3s and uracil- DNA- glycosylase affect the hypermutation frequency of hepatitis B virus cccDNA

The covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) plays a key role in the persistence of viral infection. We have previously shown that overexpression of an antiviral factor APOBEC3G (A3G) induces hypermutation in duck HBV (DHBV) cccDNA, whereas uracil- DNA- glycosylase (UNG) reduces these mutations. In this study, using cell- culture systems, we examined whether endogenous A3s and UNG affect HBV cccDNA mutation frequency. IFN?? stimulation induced a significant increase in endogenous A3G expression and cccDNA hypermutation. UNG inhibition enhanced the IFN??-mediated hypermutation frequency. Transfection of reconstructed cccDNA revealed that this enhanced hypermutation caused a reduction in viral replication. These results suggest that the balance of endogenous A3s and UNG activities affects HBV cccDNA mutation and replication competency.