Molecular Retrovirology Unit, Institut Pasteur, Paris, France.
PLoS Pathog. 2010 May 27;6(5):e1000928. doi: 10.1371/journal.ppat.1000928.
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-alpha 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 (< or = 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 approximately 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.
DNA 病毒、逆转录病毒和嗜肝 DNA 病毒，如乙型肝炎病毒 (HBV)，易受到宿主细胞 APOBEC3（A3）胞嘧啶脱氨酶对单链 DNA 的遗传编辑。在人类肝细胞中，干扰素-α至少上调了三个 A3 基因，而激活诱导的脱氨酶 (AICDA)，一种 A3 同源物，在包括丙型肝炎病毒感染在内的多种慢性炎症综合征中已有报道。然而，几乎所有关于 HBV 编辑的研究都局限于对培养上清液或血清中的病毒粒子进行分析，其中编辑基因组的频率通常较低（<或=10(-2)）。我们决定研究在原发性肝细胞癌切除过程中采集的肝硬化样本中 HBV 编辑的性质和频率。研究了 41 个肝硬化组织样本（10 个酒精性，10 个 HBV(+)，11 个 HBV(+)HCV(+)和 10 个 HCV(+)）以及 4 个正常肝脏。与正常肝脏相比，5/7 APOBEC3 基因按以下顺序显著上调：HCV(+/-)HBV>HBV>酒精性肝硬化。A3C 和 A3D 在所有组中均上调，而干扰素诱导的 A3G 在病毒相关的肝硬化中过表达，AICDA 在大约 50%的这些 HBV/HCV 样本中也过表达。虽然 AICDA 确实可以在体外编辑 HBV DNA，但 A3G 是体内主要的脱氨酶，多达 35%的 HBV 基因组被编辑。尽管这些突变谱具有高度的破坏性，但仍有一小部分基因组存活下来，导致 HBeAg 抗原血症丢失，并可能导致 HBsAg 免疫逃逸。总之，HBV 和 HCV 慢性炎症反应相关的细胞因子风暴明显上调了许多 A3 基因，A3G 显然是 HBV 的主要限制因素。尽管 A3 编辑产生的突变谱具有高度破坏性，但一小部分，特别是轻度编辑的基因组，可能有助于病毒进化甚至逃避免疫反应。
