Raimondo G, Burk R D, Lieberman H M, Muschel J, Hadziyannis S J, Will H, Kew M C, Dusheiko G M, Shafritz D A
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461.
Virology. 1988 Sep;166(1):103-12. doi: 10.1016/0042-6822(88)90151-1.
To search for events underlying reduction of peripheral viremia and integration of hepatitis B virus (HBV) DNA into the liver cell genome in long-term virus carriers with hepatocellular carcinoma, paired samples of liver and tumor tissue were analyzed by molecular hybridization and immunological methods. Most tumor tissues contained integrated viral DNA; in none was extrachromosomal HBV DNA detected. Integrated HBV DNS was also found in peritumor liver tissue in the majority of patients. However, liver of patients either with or without peripheral viremia also contained free HBV DNA and replicative intermediates. In three nonviremic patients with replicative HBV DNA in liver, viral core antigen expression was markedly reduced or absent, whereas viral envelope protein (surface antigen) expression was normal. In one case, replicative intermediates in liver were sensitive to DNase I digestion, indicating that viral DNA was not encapsidated in normal viral core particles. These results suggest that decreased or defective core antigen production can lead to reduced viremia associated with blocked virus assembly/secretion and accumulation of unencapsidated HBV DNA replicative intermediates in the liver cell. Accumulation of such HBV DNA molecular forms in the liver may lead to an increased propensity for HBV DNA to integrate into the host genome, which has been found with high frequency in hepatic neoplasms from patients infected with hepatitis B virus.
为探寻长期病毒携带者合并肝细胞癌时外周血病毒血症降低以及乙肝病毒（HBV）DNA整合至肝细胞基因组背后的机制，采用分子杂交和免疫方法对配对的肝组织和肿瘤组织样本进行了分析。多数肿瘤组织含有整合的病毒DNA；未检测到任何肿瘤组织中有染色体外HBV DNA。多数患者的肿瘤周围肝组织中也发现了整合的HBV DNA。然而，无论有无外周血病毒血症的患者肝脏中均含有游离的HBV DNA和复制中间体。在3例肝脏中有复制性HBV DNA的非病毒血症患者中，病毒核心抗原表达显著降低或缺失，而病毒包膜蛋白（表面抗原）表达正常。在1例患者中，肝脏中的复制中间体对DNase I消化敏感，表明病毒DNA未包装在正常病毒核心颗粒中。这些结果提示，核心抗原产生减少或缺陷可导致病毒血症降低，这与病毒组装/分泌受阻以及未包装的HBV DNA复制中间体在肝细胞中积累有关。肝脏中此类HBV DNA分子形式的积累可能导致HBV DNA整合至宿主基因组的倾向增加，这在乙肝病毒感染患者的肝肿瘤中已被高频发现。
