Massive APOBEC3 Editing of Hepatitis B Viral DNA in Cirrhosis

PLoS Pathogens

Carlo Battiston¹  Vincenzo Mazzaferro¹  Denise Guétard²  Jean-Pierre Vartanian²  Simon Wain-Hobson²  Michel Henry²  Rodolphe Suspène²  Marie-Ming Aynaud²  Minerva Cervantes-Gonzalez²  Pascal Pineau³  Agnès Marchio³  Anne Dejean³ 

[1] G.I. Surgery and Liver Transplantation Unit, Istituto Nazionale Tumori IRCCS, Milano, Italy;Molecular Retrovirology Unit, Institut Pasteur, Paris, France;Nuclear Organization and Oncogenesis Unit, INSERM U579, Institut Pasteur, Paris, France

关键词: Polymerase chain reaction;    Hepatitis B virus;    Gene regulation;    Cirrhosis;    Hepatitis C virus;    Alcoholics;    Transfection;    DNA;   

DOI  :  10.1371/journal.ppat.1000928

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY