Hepatitis B: modern concepts in pathogenesis ??? APOBEC3 cytidine deaminases as effectors in innate immunity against the hepatitis B virus

Abstract

APOBEC3 editing enzymes inhibit retroviruses by cytidine deamination in minus-strand cDNA, leading to G to A hypermutated proviruses, and by less well characterized inhibition of retroviral replication independently of catalysis. This review focuses on the effects of APOBEC3 enzymes on the pararetrovirus hepatitis B virus. The cytidine deaminases APOBEC3B, APOBEC3C, APOBEC3F and APOBEC3G deaminate cytidine residues in hepatitis-B-virus minus-strand cDNA, resulting in G to A hypermutated genomes in the serum of hepatitis-B-virus-infected patients. APOBEC3B, APOBEC3F and APOBEC3G directly inhibit hepatitis-B-virus reverse transcription independently of deaminase activity. In human liver, APOBEC3B, APOBEC3F and APOBEC3G are expressed to low levels, but in human primary hepatocytes stimulated with interferon-alpha, APOBEC3G is induced to levels sufficient for hepatitis-B-virus inhibition. APOBEC3B inhibits hepatitis-B-virus gene transcription, and APOBEC3B and APOBEC3G preferentially mutate the hepatitis-B-virus x gene leading to the truncated hepatitis-B-virus x variants in hepatitis-B-virus-associated liver cancer. The interferon-inducible APOBEC3G and the other APOBEC3s restrict hepatitis B virus by cytidine deamination in hepatitis-B-virus minus-strand cDNA and by direct inhibition of hepatitis-B-virus reverse transcriptase. The nuclear localized APOBEC3B is implicated in liver cancer development. To what extent these enzymes contribute to noncytolytic clearance of hepatitis B virus in vivo remains to be defined, yet the APOBEC3 cytidine deaminases are likely to play a role in these processes.