Characteristic sequence changes of hepatitis C virus genotype 2b associated with sustained biochemical response to IFN therapy
Characteristic sequence changes of hepatitis C virus genotype 2b associated with sustained biochemical response to IFN therapy
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DOI：
10.1111/j.1365-2893.2005.00511.x
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发表时间：
2005-05-01
影响因子：
2.5
通讯作者：
Watanabe, M
中科院分区：
文献类型：
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作者：
Tanabe, Y;Nagayama, K;Watanabe, M
在丙型肝炎病毒(HCV)2b型感染中，约40%的患者通过单一干扰素治疗可实现病毒根除(持续病毒应答；SVR)，而相当比例的非SVR患者表现出持续生化应答(SBR)，生化指标正常。然而，SBR的作用机制尚未建立。在这项研究中，我们分析了5名SBR患者和5名无应答(NR；持续性病毒血症和干扰素治疗后生化指标异常)的SBR患者在干扰素(干扰素)治疗前后丙型肝炎病毒2b型全长序列的系列变化。丙型肝炎病毒全基因组氨基酸总替换率SBR组高于NR组[2.22+/-0.48(10(-3)个/位/年)vs1.04+/-0.30：P=0.002]。当分析单个丙型肝炎病毒蛋白的基因变化时，SBR组NS4A氨基酸替换率显著高于0组[8.82+/-2.8(10(-3)个/位/年)vs 0：P=0.001]。SBR的这些氨基酸变化主要位于HLAI类分子的结合基序中，包括那些在日本人群中常见的分子。这些结果表明，在干扰素治疗过程中，丙型肝炎病毒的氨基酸变化较大，与SBR的建立有关。虽然这些变化的功能意义有待进一步研究，但SBR患者NS4A的氨基酸变化主要位于HLAI类结合基序，这一发现说明了丙型肝炎病毒基因组CTL逃逸突变在SBR肝炎活动减少中的潜在作用。
In hepatitis C virus (HCV) genotype 2b infection, viral eradication ( sustained viral response; sVR) is obtained in about 40% by interferon monotherapy, whereas a considerable proportion of non-sVR patients exhibit sustained biochemical response (sBR) showing normal biochemical values despite persistent viraemia. However, the mechanism of sBR has not yet been established. In this study, we analysed serial changes in full-length sequences of HCV genotype 2b before and after interferon (IFN) therapy in five patients with sBR and five with no response (NR; persistent viraemia and abnormal biochemical values after IFN therapy). The overall substitution rate of amino acids in the full-length HCV genome was higher in the sBR group than in the NR group [2.22 +/- 0.48 ( 10(-3) changes/ site/ year) vs 1.04 +/- 0.30: P = 0.002]. When the genetic changes were analysed for individual HCV proteins, the sBR group had significantly higher substitution rates of amino acid in NS4A [8.82 +/- 2.80 (10(-3) changes/ site/ year) vs 0: P = 0.001]. These amino acid changes in sBR were mainly located in the binding motifs of HLA class I molecules including those frequently found in the Japanese population. These results demonstrated that the greater amino acid changes of HCV arising during interferon therapy are associated with the establishment of sBR. Although functional significance of these changes awaits further investigation, the finding that amino acid changes in NS4A in sBR patients are mainly located in the HLA class I binding motifs illustrated the potential roles of the escape mutations of HCV genome from CTLs in the decreasing activities of hepatitis in sBR.