Complex HBV populations with mutations in core promoter, C gene, and pre-S region are associated with development of cirrhosis in long-term renal transplant recipients
Complex HBV populations with mutations in core promoter, C gene, and pre-S region are associated with development of cirrhosis in long-term renal transplant recipients
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DOI：
10.1053/jhep.2002.30698
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发表时间：
2002-02-01
期刊：
影响因子：
13.5
通讯作者：
Meisel, H
中科院分区：
文献类型：
--
作者：
Preikschat, P;Günther, S;Meisel, H
慢性B型肝炎病毒（HBV）感染的长期免疫抑制肾移植受者经常发展为肝硬化（LC）和终末期肝病（ESLD）。本研究调查了这些患者中与临床病程相关的特定HBV突变体的积累和持续性（n = 38;平均随访时间为3.5年）。通过聚合酶链反应（PCR）片段的长度多态性（中位数，每例患者6.5份血清样本）以及346个全长HBV基因组的克隆和部分测序，对HBV进行纵向分析。14例患者（第1组）发生LC或死于ESLD，而24例患者（第2组）在随访期间未显示LC的证据。LC和ESLD的发生与HBV突变群体的持续存在有关，这些突变群体的特征是核心启动子缺失/插入加上C基因缺失和/或前S区缺失（第1组86% vs第2组17%; P <0.0001）。不含这些突变或仅含核心启动子突变的HBV主要见于第2组（第1组14% vs第2组75%）。在感染核心启动子突变体的患者中，C基因和/或前S区缺失的额外出现和持续存在伴随或随后发生LC和ESLD。突变以各种组合分布在单个基因组上，导致病毒群体的高度复杂性。总之，这些数据表明，积累和持续存在的特定HBV群体的突变特征在3个亚基因组区域发挥作用的发病机制，LC和ESLD在长期肾移植受者。
Long-term immunosuppressed renal transplant recipients with chronic hepatitis B virus (HBV) infection often develop liver cirrhosis (LC) and end-stage liver disease (ESLD). This study investigated accumulation and persistence of specific HBV mutants in relation to the clinical course in these patients (n = 38; mean follow-up, 3.5 years). HBV was analyzed longitudinally via length polymorphism of polymerase chain reaction (PCR) fragments (median, 6.5 serum samples per patient) as well as by cloning and partial sequencing of 346 full-length HBV genomes. Fourteen patients (group 1) developed LC or died from ESLD, whereas 24 patients (group 2) showed no evidence of LC during follow-up. Development of LC and ESLD was associated with persistence of HBV mutant populations characterized by deletions/insertions in core promoter plus deletions in the C gene and/or deletions in the pre-S region (86% of group 1 vs. 17% of group 2; P < .0001). HBV without these mutations or with core promoter mutations alone were predominantly found in group 2 (14% of group 1 vs. 75% of group 2). In patients infected with core promoter mutants, the additional appearance and persistence of deletions in the C gene and/or the pre-S region were accompanied or followed by development of LC and ESLD. The mutations were distributed on individual genomes in various combinations, leading to a high complexity of the virus population. In conclusion, these data suggest that accumulation and persistence of specific HBV populations characterized by mutations in 3 subgenomic regions play a role in pathogenesis of LC and ESLD in long-term renal transplant recipients.