Rosmorduc O, Sirma H, Soussan P, Gordien E, Lebon P, Horisberger M, Br Chot C, Kremsdorf D
J Gen Virol. 1999 May;80 ( Pt 5):1253-1262. doi: 10.1099/0022-1317-80-5-1253.
Chronic hepatitis B treatment has been significantly improved by interferon (IFN) treatment. However, some studies have suggested that hepatitis B virus (HBV) might have a direct effect on the resistance to IFN. Defective particles, generated by spliced HBV RNA and associated with chronic hepatitis B, have been previously characterized; expression of these particles leads to cytoplasmic accumulation of the capsid protein. The aim of this study was to investigate the role of these defective genomes in IFN resistance. The global antiviral activity of IFN was studied by virus yield reduction assays, the expression of three IFN-induced antiviral proteins was analysed by Western blotting and confocal microscopy, and the regulation of MxA gene expression was studied by Northern blotting and the luciferase assay, in Huh7 cells transfected with a complete or the defective HBV genome. Results showed that the expression of the defective genome reduces the antiviral activity of IFN and that this modulation involves a selective inhibition of MxA protein induction by the HBV capsid protein. Our results also show the trans-suppressive effect of the HBV capsid on the MxA promoter, which might participate in this phenomenon. In conclusion, this study shows a direct interplay between the IFN-sensitive pathway and the capsid protein and might implicate this defective HBV genome in virus persistence.
干扰素（IFN）治疗显著改善了慢性乙型肝炎的治疗效果。然而，一些研究表明，乙型肝炎病毒（HBV）可能对IFN耐药性有直接影响。由剪接的HBV RNA产生并与慢性乙型肝炎相关的缺陷颗粒，此前已有特征描述；这些颗粒的表达导致衣壳蛋白在细胞质中积累。本研究的目的是探讨这些缺陷基因组在IFN耐药中的作用。通过病毒产量降低试验研究IFN的整体抗病毒活性，通过蛋白质印迹法和共聚焦显微镜分析三种IFN诱导的抗病毒蛋白的表达，并通过Northern印迹法和荧光素酶试验研究MxA基因表达的调控，在转染了完整或缺陷HBV基因组的Huh7细胞中进行。结果表明，缺陷基因组的表达降低了IFN的抗病毒活性，且这种调节涉及HBV衣壳蛋白对MxA蛋白诱导的选择性抑制。我们的结果还显示了HBV衣壳对MxA启动子的反式抑制作用，这可能参与了这一现象。总之，本研究显示了IFN敏感途径与衣壳蛋白之间的直接相互作用，可能意味着这种缺陷HBV基因组与病毒持续存在有关。
