Paterson M, Laxton C D, Thomas H C, Ackrill A M, Foster G R
Imperial College of Medicine at St. Mary's Campus, London, England.
Gastroenterology. 1999 Nov;117(5):1187-97. doi: 10.1016/s0016-5085(99)70405-1.
BACKGROUND & AIMS: Patients with chronic hepatitis C virus infection are commonly treated with interferon alfa (IFN-alpha), but the long-term response rate is poor. A region of NS5A of hepatitis C virus genotype 1 (the ISDR) has been associated with treatment outcome in some patients. NS5A binds to and inhibits PKR in vitro and inhibits IFN-alpha in human cells. We examined the effects of the NS5A protein from patients who did or did not respond to IFN-alpha to determine whether NS5A from IFN-alpha nonresponders inhibited the effects of IFN-alpha in vitro.
We cloned NS5A from patients who had well-characterized responses to IFN-alpha and expressed them in a human fibroblast cell line under the control of an inducible promoter. The NS5A expression levels were controlled, and the effects of different proteins on the protective actions of IFN-alpha against encephalomyocarditis virus were investigated.
NS5A expression blocked the antiviral effects of IFN-alpha in human cells. This inhibition was dependent on the level of NS5A expression. Although ISDR changes gave only small differences in IFN-alpha inhibition, clones derived from a patient who did not respond to IFN-alpha and one who did respond to treatment differed greatly: the clones from a patient with response to IFN-alpha were much more inhibitory than those derived from the patient with no response.
The inhibition of the antiviral effects of IFN-alpha by NS5A is not regulated exclusively by the ISDR, and the effects of NS5A in vitro do not correlate with treatment outcomes.
慢性丙型肝炎病毒感染患者通常接受干扰素α（IFN-α）治疗，但长期缓解率较低。丙型肝炎病毒1型的NS5A区域（即ISDR）在一些患者中与治疗结果相关。NS5A在体外可结合并抑制PKR，在人细胞中可抑制IFN-α。我们检测了对IFN-α有反应或无反应患者的NS5A蛋白的作用，以确定来自IFN-α无反应者的NS5A在体外是否抑制IFN-α的作用。
我们从对IFN-α有明确反应的患者中克隆NS5A，并在诱导型启动子控制下在人成纤维细胞系中表达。控制NS5A的表达水平，研究不同蛋白对IFN-α抗脑心肌炎病毒保护作用的影响。
NS5A的表达阻断了IFN-α在人细胞中的抗病毒作用。这种抑制作用取决于NS5A的表达水平。尽管ISDR的变化在IFN-α抑制方面仅有微小差异，但来自一名对IFN-α无反应患者和一名有反应患者的克隆有很大不同：对IFN-α有反应患者的克隆比无反应患者的克隆抑制作用更强。
NS5A对IFN-α抗病毒作用的抑制并非仅由ISDR调节，且NS5A在体外的作用与治疗结果无关。
