Antiviral factor AID/APOBECs and Hepatitis B virus-related hepatocellular carcinogenesis

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Recent studies have revealed that AID/APOBEC cytidine deaminase family members can induce C-to-U hypermutation on viral genome and restrict replication of various types of virus including HBV. Uracil residues in DNA are removed by base excision repair (BER) enzyme, uracil DNA glycosylase (UNG) when cytidine deamination is occurred in host genome.Here, we investigated whether uracil residues were removed by UNG from HBV and DHBV DNAs using in vitro cell culture system. When UNG activity was inhibited by the expression of UNG inhibitory protein (UGI), the APOBEC3G-mediated hypermutation of HBV nucleocapsid DNA was enhanced. The enhanced hypermutation by APOBEC3G and UGI was also observed in DHBV cccDNA, which was more frequent than in nucleocapsid DNA. We also found that overexpression of chicken AID caused hypermutation and reduction of DHBV cccDNA levels. These results indicate that UNG excises uracils from viral genome deaminated by AID/APOBEC protein during or after cccDNA formation.