Hepatitis B Virus DNA is Subject to Extensive Editing by the Human Deaminase APOBEC3C

Unlabelled: APOBEC3G (A3G) and APOBEC3C (A3C), 2 members of the APOBEC family, are cellular cytidine deaminases displaying broad antiretroviral activity. A3G inhibits hepatitis B virus (HBV) production by interfering with HBV replication without hypermutating the majority of HBV genomes. In contrast, A3C has little effect on HBV DNA synthesis. The aim of this study was to further dissect the mechanisms by which A3G and A3C interfere with the HBV life cycle. Immunoprecipitation experiments demonstrated that both A3G and A3C bind to the HBV core protein. A ribonuclease (RNase) treatment resulted in the nearly complete dissociation of the HBV core protein from A3G, whereas the HBV core-A3C complex was more stable. Interestingly, the majority of the newly synthesized HBV DNA genomes displayed extensive G-to-A mutations in the presence of A3C, whereas no A3C-induced HBV RNA mutations were detected. These findings support a model in which the RNA-dependent entrapment of A3G into the preassembly complex hampers subsequent steps in capsid formation. On the other hand, A3C is readily packaged into replication-competent capsids and efficiently deaminates newly synthesized HBV DNA.

Conclusion: These findings demonstrate that HBV is highly vulnerable to the editing activity of an endogenous human deaminase and suggest that A3C could contribute to innate anti-HBV host responses.