Molecular Immuno-Oncology Laboratory, Faculty of Medicine, Monastir, Tunisia.
J Med Virol. 2009 Dec;81(12):2021-8. doi: 10.1002/jmv.21641.
In the non-structural protein 5A (NS5A) of hepatitis C virus (HCV), mutations within the interferon sensitivity-determining region (ISDR), the PKR-binding domain (PKR-BD), the variable region 3 (V3), and the interferon/ribavirin resistance-determining region (IRRDR) have been correlated with the IFN-based therapy response. In Tunisia, where a high prevalence of HCV-1b has been found, no data regarding the implication of NS5A in treatment response were available. The current study examined the relationship between the pre-treatment mutation number within ISDR, PKR-BD, V3, IRRDR, as well as in the entire ISDR-V3 region of NS5A (aa 2209-2379) and the response to the 48-week course of combined IFN plus ribavirin therapy in 15 HCV-1b-infected Tunisian patients. Referring to HCV-J sequence, a significant high genetic variability was observed within PKR-BD in the sustained virological responder patients compared to non-responders (P = 0.040). More importantly, when considering the entire region from ISDR to V3, referred to as NS5A(ISDR-V3), a clear difference in the mutation number was observed between sustained virological responders (19.6 +/- 3.16) and non-responders (15.0 +/- 1.41) (P = 0.002). Additionally, a more detailed analysis of NS5A(ISDR-V3) region revealed an elevated degree of mutation rate within the region located between amino acids 2282 and 2308 (P = 0.0006). Interestingly, an analysis of specific amino acid variations defined proline and serine at position 2300 as signature patterns for sensitive and resistant strains, respectively. The genetic variability within the NS5A region of HCV-1b strains was associated with the response to the combined IFN plus ribavirin therapy in our Tunisian cohort.
在丙型肝炎病毒（HCV）的非结构蛋白 5A（NS5A）中，干扰素敏感性决定区（ISDR）、PKR 结合域（PKR-BD）、可变区 3（V3）和干扰素/利巴韦林耐药决定区（IRRDR）内的突变与基于 IFN 的治疗反应相关。在发现 HCV-1b 高流行率的突尼斯，没有关于 NS5A 在治疗反应中的作用的数据。本研究检查了 NS5A 的 ISDR、PKR-BD、V3、IRRDR 内以及整个 ISDR-V3 区域（aa2209-2379）的治疗前突变数量与 15 例感染 HCV-1b 的突尼斯患者接受联合 IFN 加利巴韦林 48 周治疗的反应之间的关系。参考 HCV-J 序列，在持续病毒学应答患者中，与非应答者相比，在 PKR-BD 内观察到显著的高遗传变异性（P=0.040）。更重要的是，当考虑到从 ISDR 到 V3 的整个区域，称为 NS5A(ISDR-V3)时，在持续病毒学应答者（19.6 +/- 3.16）和非应答者（15.0 +/- 1.41）之间观察到突变数量的明显差异（P=0.002）。此外，对 NS5A(ISDR-V3)区域的更详细分析显示，位于氨基酸 2282 和 2308 之间的区域内的突变率升高（P=0.0006）。有趣的是，对特定氨基酸变异的分析表明，位置 2300 处的脯氨酸和丝氨酸分别是敏感和耐药株的特征模式。在我们的突尼斯队列中，HCV-1b 株的 NS5A 区域内的遗传变异性与联合 IFN 加利巴韦林治疗的反应相关。
