Massive APOBEC3 Editing of Hepatitis B Viral DNA in Cirrhosis

Abstract

DNA viruses, retroviruses and hepadnaviruses, such as hepatitis B virus (HBV), are vulnerable to genetic editing of single stranded DNA by host cell APOBEC3 (A3) cytidine deaminases. At least three A3 genes are up regulated by interferon-α in human hepatocytes while ectopic expression of activation induced deaminase (AICDA), an A3 paralog, has been noted in a variety of chronic inflammatory syndromes including hepatitis C virus infection. Yet virtually all studies of HBV editing have confined themselves to analyses of virions from culture supernatants or serum where the frequency of edited genomes is generally low (≤10−2). We decided to look at the nature and frequency of HBV editing in cirrhotic samples taken during removal of a primary hepatocellular carcinoma. Forty-one cirrhotic tissue samples (10 alcoholic, 10 HBV+, 11 HBV+HCV+ and 10 HCV+) as well as 4 normal livers were studied. Compared to normal liver, 5/7 APOBEC3 genes were significantly up regulated in the order: HCV±HBV>HBV>alcoholic cirrhosis. A3C and A3D were up regulated for all groups while the interferon inducible A3G was over expressed in virus associated cirrhosis, as was AICDA in ∼50% of these HBV/HCV samples. While AICDA can indeed edit HBV DNA ex vivo, A3G is the dominant deaminase in vivo with up to 35% of HBV genomes being edited. Despite these highly deleterious mutant spectra, a small fraction of genomes survive and contribute to loss of HBeAg antigenemia and possibly HBsAg immune escape. In conclusion, the cytokine storm associated with chronic inflammatory responses to HBV and HCV clearly up regulates a number of A3 genes with A3G clearly being a major restriction factor for HBV. Although the mutant spectrum resulting from A3 editing is highly deleterious, a very small part, notably the lightly edited genomes, might help the virus evolve and even escape immune responses.

Molecular Determinants of Hepatitis B and D Virus Entry Restriction in Mouse Sodium Taurocholate Cotransporting Polypeptide

“…In fact, productive infection of HBV of human hepatocytes critically depends on some liver-specific transcription factors, e.g., HNF4A and HLF (42). APOBEC3 was shown to be a major cellular restriction factor(s) for HBV in vitro and in vivo (43)(44)(45). The undetectable HBV infection that we observed in cells other than HepG2-NTCP may also be attributable to the missing of liver-specific transcription factors or the present of postentry cellular restriction factor(s) presented in these cells.…”

The MOV10 Helicase Inhibits LINE-1 Mobility

“…To control massively activated LINE-1, germ line cells express a special type of small RNA named piRNA (piwi-interacting RNA) that arms Piwi (P-element induced wimpy testis) proteins to suppress LINE-1 (25,26). Furthermore, it has been reported that APOBEC3 (apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3) proteins, which inhibit the infection of a broad range of viruses particularly retroviruses (27)(28)(29)(30)(31), also provide another mechanism to control LINE-1 (32)(33)(34). It appears that cells manage to use the same mechanism to protect themselves from either extracellular or intracellular insults that share common biochemical features.…”

Genetic Editing of Herpes Simplex Virus 1 and Epstein-Barr Herpesvirus Genomes by Human APOBEC3 Cytidine Deaminases in Culture and In Vivo

“…Since the reaction product is uridine (dU), A3 activity results in DNA peppered by C 3 U substitutions, referred to as hypermutants. Editing can range from a few cytidine targets to over 80% (2,3,8,16,26,29,30,49,54). To a good first approximation, all A3 enzymes preferentially edit ssDNA when the edited base is 5Ј flanked by thymidine or cytidine, i.e., TpC and CpC.…”

“…To a good first approximation, all A3 enzymes preferentially edit ssDNA when the edited base is 5Ј flanked by thymidine or cytidine, i.e., TpC and CpC. In contrast, AICDA prefers GpC and ApC (2,3,9,17,27,39,49,54).…”