Massive APOBEC3 editing of hepatitis B viral DNA in cirrhosis.
Massive APOBEC3 editing of hepatitis B viral DNA in cirrhosis.
复制标题
DOI：
10.1371/journal.ppat.1000928
复制
发表时间：
2010-05-27
期刊：
影响因子：
6.7
通讯作者：
Wain-Hobson S
中科院分区：
文献类型：
--
作者：
Vartanian JP;Henry M;Marchio A;Suspène R;Aynaud MM;Guétard D;Cervantes-Gonzalez M;Battiston C;Mazzaferro V;Pineau P;Dejean A;Wain-Hobson S
DNA病毒、逆转录病毒和肝炎病毒，如乙型肝炎病毒（HBV），很容易被宿主细胞APOBEC3 （A3）胞苷脱氨酶对单链DNA进行基因编辑。在人肝细胞中，至少有三个A3基因被干扰素-α上调，而激活诱导脱氨酶（AICDA）的异位表达，是A3的一种类似物，已在包括丙型肝炎病毒感染在内的多种慢性炎症综合征中被注意到。然而，几乎所有关于HBV编辑的研究都局限于对来自培养上清或血清的病毒粒子的分析，其中编辑基因组的频率通常较低（≤10−2）。我们决定研究原发性肝细胞癌切除期间采集的肝硬化样本中HBV编辑的性质和频率。研究了41例肝硬化组织样本（酒精性10例、HBV+ 10例、HBV+HCV+ 11例、HCV+ 10例）和4例正常肝脏。与正常肝脏相比，5/7个APOBEC3基因显著上调，顺序为：HCV±HBV>HBV>酒精性肝硬化。A3C和A3D在所有组中上调，而干扰素诱导的A3G在病毒相关肝硬化中过表达，在这些HBV/HCV样本中约50%的AICDA也是如此。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，高达35%的HBV基因组被编辑。尽管这些高度有害的突变谱，一小部分基因组存活下来，并导致HBeAg抗原血症的丧失和可能的HBsAg免疫逃逸。综上所述，与HBV和HCV慢性炎症反应相关的细胞因子风暴明显上调了多个A3基因，其中A3G显然是HBV的主要限制因子。虽然A3编辑产生的突变谱是高度有害的，但很小一部分，特别是轻度编辑的基因组，可能有助于病毒进化，甚至逃脱免疫反应。逆转录病毒和肝炎病毒如乙型肝炎病毒（HBV）易受宿主细胞单链DNA胞苷脱氨酶的突变。结果是带有尿嘧啶残基的超突变病毒。虽然可能有11种这样的人类酶，但主要的参与者属于22号染色体上的7个基因APOBEC3簇，其中一些可以被抗病毒干扰素激活。我们研究了41例原发性肝细胞癌手术切除后肝硬化样本中HBV编辑的性质和频率。大量APOBEC3基因的激活顺序为HCV±HBV>HBV>酒精性肝硬化。我们观察到APOBEC3G是体内高达35%的HBV编辑基因组的主要限制因子。在APOBEC3编辑产生的HBV突变体中，我们发现一小部分轻度APOBEC3G编辑的基因组可以影响HBV在体内的复制并可能免疫逃逸。
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. Retroviruses and hepadnaviruses such as hepatitis B virus (HBV) are vulnerable to mutation by host cell single stranded DNA cytidine deaminases. The result is hypermutated viral peppered with uracil residues. While there are potentially 11 such human enzymes, the major players belong to the 7 gene APOBEC3 cluster on chromosome 22, some of which can be activated by anti-viral interferons. We investigated the nature and frequency of HBV editing in 41 cirrhotic samples following surgical removal of primary hepatocellular carcinoma. Numerous APOBEC3 genes were activated in the decreasing order HCV±HBV>HBV>alcoholic cirrhosis. We observed that APOBEC3G was the dominant restricting factor in vivo with up to 35% of HBV edited genomes. Among the HBV mutants generated by APOBEC3 editing, we found a small fraction of lightly APOBEC3G edited genomes that can impact HBV replication in vivo and possibly immune escape.
登录
查看更多内容
影响因子：
3.8
作者：
Chiou, HL;Lee, TS;Ho, MS
通讯作者：
Ho, MS
影响因子：
8
作者：
Endo, Y.;Marusawa, H.;Chiba, T.
通讯作者：
Chiba, T.
影响因子：
3.7
作者：
Henry M;Guétard D;Suspène R;Rusniok C;Wain-Hobson S;Vartanian JP
通讯作者：
Vartanian JP
影响因子：
64.8
作者：
Esnault, C;Heidmann, O;Schwartz, O
通讯作者：
Schwartz, O
影响因子：
29.4
作者：
Endo, Yoko;Marusawa, Hiroyuki;Chiba, Tsutomu
通讯作者：
Chiba, Tsutomu