Direct Cytopathic Effects of Particular Hepatitis B Virus Genotypes in Severe Combined Immunodeficiency Transgenic With Urokinase-Type Plasminogen Activator Mouse With Human Hepatocytes
Direct Cytopathic Effects of Particular Hepatitis B Virus Genotypes in Severe Combined Immunodeficiency Transgenic With Urokinase-Type Plasminogen Activator Mouse With Human Hepatocytes
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DOI：
10.1053/j.gastro.2008.10.048
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发表时间：
2009-02-01
期刊：
影响因子：
29.4
通讯作者：
Mizokami, Masashi
中科院分区：
文献类型：
--
作者：
Sugiyama, Masaya;Tanaka, Yasuhito;Mizokami, Masashi
背景与目的：关于乙肝病毒的直接细胞病变效应及其与特定病毒基因型或基因突变的关系，目前知之甚少。我们研究了携带人类肝细胞的严重联合免疫缺陷转基因和尿激酶型纤溶酶原激活剂转基因小鼠在病毒复制、抗原表达和组织病理学方面与乙肝病毒基因型相关的差异。方法：用从感染前小鼠血清或患者血清中回收的不同基因型的野生型病毒株(每株3株)接种小鼠。结果：感染22~25周的小鼠肝组织学观察显示，氧化应激通过反式生长因子-β1信号转导肝星状细胞活化，导致人源化部分肝细胞大量磨玻璃样改变，而乙肝病毒A2和B1均未见此现象。在接种后6~8周，感染HBVC2的小鼠血清中的HBVDNA水平最高，分别为10(9)、10(7)和10(4)log Copies/mL(P<0.05)。Hb核心相关抗原的排泄趋势在各基因型间相似，而Hb表面抗原的排泄在HBVA2中更为明显，其次是HBVC2，而在HBVB1中的分泌则更少。在HBVB1中引入前C区终止密码子突变导致病毒复制、抗原表达和类似于HBVC2的组织病理学图像显著增加。结论：通过人源化体内模型，我们发现不同的HBV型，甚至特定的变异，会导致不同的病毒学和组织病理学结果，提示在免疫抑制条件下，特定的HBV变异体可能是直接的细胞病变。
Background & Aims: Little is known about the direct cytopathic effect of hepatitis B virus (HBV) and its association with particular viral genotypes or genetic mutations. We investigate HBV genotype-related differences in viral replication, antigen expression, and histopathology in severe combined immunodeficiency transgenic with urokinase-type plasminogen activator mice harboring human hepatocytes. Methods: Mice were inoculated with wild-type of different genotype strains (3 for each HBV/A2, B1, and C2) recovered from preinfected-mice sera or patient sera. Results: Histologic analysis of mice infected with HBV/C2 for 22-25 weeks showed abundant ground-glass appearance of the hepatocytes and fibrosis in the humanized part of the murine liver owing to the activation of hepatic stellate cells mediated by oxidative stress through tran forming growth factor-beta 1 signaling, whereas neither was observed with HBV/A2 and B1. The HBV-DNA level in sera was the highest in mice infected with HBV/C2 compared with those with HBV/A2 and HBV/B1 (10(9),10(7), and 10(4) log copies/mL, respectively, P < .05) during 6 - 8 weeks postinoculation. HB core-related antigen excretion had a similar trend among the genotypes, whereas secretion of HB surface antigen was more pronounced for HBV/A2 followed by HBV/C2 and much less for HBV/B1. Introduction of precore stop-codon mutation in the HBV/B1 caused a significant increase in viral replication, antigen expression, and a histopathologic picture similar to HBV/C2. Conclusions: By using a humanized in vivo model, we show that different HBV genotypes and even particular mutations resulted in different virologic and histopathologic outcomes of infection, indicating that particular genetic variants of HBV may be directly cytopathic in immunosuppressive conditions.