Impaired intrahepatic hepatitis B virus productivity contributes to low viremia in most HBeAg-negative patients
Impaired intrahepatic hepatitis B virus productivity contributes to low viremia in most HBeAg-negative patients
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DOI：
10.1053/j.gastro.2007.06.057
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发表时间：
2007-09-01
期刊：
影响因子：
29.4
通讯作者：
Petersen, Joerg
中科院分区：
文献类型：
--
作者：
Volz, Tassilo;Lutgehetmann, Marc;Petersen, Joerg
背景与目的：了解调节乙型肝炎病毒（HBV）共价闭合环状DNA （cccDNA）转录活性的因素可能有助于理解病毒衰变的机制，以及这些过程如何在慢性HBV感染患者中受阻。方法：对119例初治慢性感染患者（42例hbeag阳性，77例hbeag阴性）进行肝活检，检测HBV转录和复制活性。结果：与hbeag阳性患者相比，hbeag阴性患者血清HBV DNA （-4 log）、肝内HBV DNA （-2 log）和cccDNA （-1 log）的中位数明显降低。尽管在所有患者中发现肝内子代病毒粒子数量与血清HBV DNA之间存在良好的相关性，但在hbeag阴性个体中，cccDNA水平与血清滴度无关。对HBV RNA转录物的分析表明，hbeag阴性个体的病毒粒子生产力受损是由于每个cccDNA产生的基因组前RNA的稳态水平较低。有趣的是，当标准化cccDNA含量时，hbeag阳性和hbeag阴性患者的preS/S RNA水平和血清HBsAg浓度没有差异，这表明hbeag阴性患者的亚病毒颗粒产生没有受损，并与cccDNA水平相关。尽管大多数hbeag阴性个体携带cccDNA前核和/或基核启动子突变，但这些变异的发生并不是病毒复制减少的原因。相反，用核心启动子突变体替代野生型cccDNA重新建立了高病毒粒子生产力。结论：HBeAg阴性个体较低的病毒血症不仅是由于cccDNA含量较低，而且是由于病毒粒子的生产力受损，这可能在不出现HBeAg变异的情况下发生，也不会影响HBsAg的产生。
Background& Aims: Knowledge of factors regulating transcriptional activity of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) may help in understanding mechanisms of viral decay and how these processes are thwarted in chronically HBV-infected patients. Methods: Liver biopsies from 119 treatment-naive chronically infected patients (42 HBeAg-positive and 77 HBeAg-negative) were determined for HBV transcriptional and replicative activity. Results: Significantly lower median serum HBV DNA (-4 log), intrahepatic HBV DNA (-2 log), and cccDNA (-1 log) amounts were measured in HBeAg-negative versus HBeAg-positive patients. Despite a good correlation found between intrahepatic amounts of progeny virions and serum HBV DNA in all patients, cccDNA levels did not correlate with serum titers in HBeAg-negative individuals. Analysis of HBV RNA transcripts showed that impaired virion productivity in HBeAg-negative individuals was due to lower steady-state levels of pregenomic RNA produced per cccDNA. Interestingly, preS/S RNA levels and serum HBsAg concentrations did not differ between HBeAg-positive and HBeAg-negative patients when normalized for cccDNA contents, showing that subviral particle production was not impaired in HBeAg-negative patients and correlated with cccDNA levels. Although the majority of HBeAgnegative individuals harbored cccDNA with common precore and/or basal core promoter mutations, occurrence of these variants was not responsible for reduced viral replication. Instead, replacement of wild-type cccDNA with core promoter mutants reestablished high virion productivity. Conclusions: Lower viremia in HBeAg-negative individuals is not only due to lower cccDNA content but also to impaired virion productivity, which can arise without emergence of HBeAg variants and without affecting HBsAg production.