McKechnie V M, Mills P R, McCruden E A
Division of Virology, Institute of Biomedical and Life Sciences, University of Glasgow, Scotland.
J Med Virol. 2000 Apr;60(4):367-78.
Patients infected with hepatitis C virus (HCV) genotype 3 have a better response to interferon-alpha (IFN-alpha) therapy than those infected with genotype 1. There are extensive sequence differences between genotypes in the 3' half of the NS5a gene. An association between IFN-alpha response and the interferon sensitivity-determining region (ISDR) (amino acids 2209-2248) of HCV genotype 1b has been described [Enomoto et al. (1996) New England Journal of Medicine 334:771-776]. A prospective study was conducted to determine whether the derived NS5A amino acid sequence or quasi-species diversity could predict response to IFN-alpha therapy. Serum samples were obtained before, during, and after treatment from 35 IFN-alpha-treated patients chronically infected with HCV (eight with type1b,13 with type1a, and 14 with type3a). Nucleotide sequences were determined, and amino acid sequences corresponding to residues 2178-2390 of the polyprotein were derived. Quasi-species complexity was analysed by amplification of the ISDR region (2270-2403), followed by single-stranded conformation polymorphism (SSCP). No amino acid sequence that could be used to predict response to treatment was found, and there was no selection of specific amino acid residues during treatment. A striking lack of variability was seen in HCV genotype 3a, but the small degree of variation could suggest an effect on response. SSCP showed that variation in the predominant NS5a sequence occurred in the presence and absence of therapeutically administered IFN-alpha. HCV quasi-species diversity pretreatment did not predict IFN-alpha treatment outcome. The conclusion of the study is that the amino acid sequence of NS5a cannot be used to predict the efficacy of treatment with IFN-alpha in HCV-infected patients in Scotland. No evidence was found to support the selection of IFN-alpha-resistant strains in the NS5a gene.
丙型肝炎病毒（HCV）基因3型感染者对α干扰素（IFN-α）治疗的反应比基因1型感染者更好。NS5a基因3'端的不同基因型之间存在广泛的序列差异。已有研究描述了HCV基因1b型的α干扰素反应与干扰素敏感性决定区（ISDR）（氨基酸2209 - 2248）之间的关联[榎本等人（1996年）《新英格兰医学杂志》334:771 - 776]。进行了一项前瞻性研究，以确定推导的NS5A氨基酸序列或准种多样性是否可预测对α干扰素治疗的反应。从35例接受α干扰素治疗的慢性HCV感染者（8例基因1b型、13例基因1a型和14例基因3a型）治疗前、治疗期间和治疗后获取血清样本。测定核苷酸序列，并推导与多聚蛋白2178 - 2390位残基对应的氨基酸序列。通过扩增ISDR区域（2270 - 2403），随后进行单链构象多态性（SSCP）分析准种复杂性。未发现可用于预测治疗反应的氨基酸序列，且治疗期间未选择特定氨基酸残基。在HCV基因3a型中观察到显著缺乏变异性，但小程度的变异可能提示对反应有影响。SSCP显示，在给予治疗性α干扰素前后，主要NS5a序列均存在变异。HCV准种多样性预处理不能预测α干扰素治疗结果。该研究的结论是，NS5a的氨基酸序列不能用于预测苏格兰HCV感染患者α干扰素治疗的疗效。未发现支持在NS5a基因中选择α干扰素耐药株的证据。
