Zeuzem S, Lee J H, Roth W K
Medizinische Klinik II, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt a.M., Germany.
Hepatology. 1997 Mar;25(3):740-4. doi: 10.1002/hep.510250341.
The response rate to interferon alfa (IFN-alpha) in patients infected with hepatitis C virus (HCV) genotype 1 isolates is poor. A region associated with sensitivity to IFN has been identified in subtype HCV-1b isolates from Japanese patients in the carboxyterminal half of the nonstructural protein NS5A (between codon 2209 and 2248). HCV-1b isolates with at least four amino acid changes in this region compared with the HCV-1b prototype sequence were sensitive, whereas isolates identical to the prototype sequence were resistant to IFN-alpha. Patients infected with HCV-1b isolates carrying 1 to 3 mutations in NS5A(2209-2248) showed an intermediate response pattern. Because of the large geographical differences observed for HCV it is unknown whether this putative IFN-alpha sensitivity determining region is also predictive for European isolates. We analyzed 32 patients chronically infected with HCV-1a or HCV-1b isolates who were treated with 3 million units of recombinant IFN-alpha three times per week for 1 year. Before initiation, during, and after treatment serum HCV-RNA levels were assessed by a quantitative reverse-transcription polymerase chain reaction (RT-PCR) assay. The amino acid sequence of NS5A(2209-2248)was determined by direct sequencing of the PCR-amplified HCV genome and was compared with the reference sequence HCV-J. In patients chronically infected with subtype HCV-1a or HCV-1b the initial or sustained response to IFN-alpha was not related to the number of amino acid substitutions in the NS5A(2209-2248) region. In addition, the number of amino acid changes in NS5A(2209-2248) was not related to pretreatment HCV-RNA serum levels. In three patients with a pronounced initial decline of HCV-RNA levels (>3 log) sequence analyses of NS5A(2209-2248) were performed before and after therapy. Compared with the pretreatment amino acid sequence the HCV isolates of these patients revealed more mutations in the NS5A(2209-2248) region after therapy. These findings from European patients indicate that the NS5A(2209-2248) region of HCV does not represent a common interferon sensitivity determining region.
丙型肝炎病毒（HCV）基因1型分离株感染患者对干扰素α（IFN-α）的应答率较低。在日本患者的HCV-1b亚型分离株的非结构蛋白NS5A的羧基末端一半区域（密码子2209和2248之间）已鉴定出一个与IFN敏感性相关的区域。与HCV-1b原型序列相比，该区域至少有四个氨基酸变化的HCV-1b分离株对IFN敏感，而与原型序列相同的分离株对IFN-α耐药。感染在NS5A（2209-2248）区域携带1至3个突变的HCV-1b分离株的患者表现出中间应答模式。由于观察到HCV存在较大的地理差异，尚不清楚这个假定的IFN-α敏感性决定区域是否也能预测欧洲分离株的情况。我们分析了32例慢性感染HCV-1a或HCV-1b分离株的患者，他们接受每周三次、每次300万单位重组IFN-α治疗，为期1年。在治疗开始前、治疗期间和治疗后，通过定量逆转录聚合酶链反应（RT-PCR）测定血清HCV-RNA水平。通过对PCR扩增的HCV基因组进行直接测序确定NS5A（2209-2248）的氨基酸序列，并与参考序列HCV-J进行比较。在慢性感染HCV-1a或HCV-1b亚型的患者中，对IFN-α的初始或持续应答与NS5A（2209-2248）区域的氨基酸取代数量无关。此外，NS5A（2209-2248）中的氨基酸变化数量与治疗前HCV-RNA血清水平无关。对三名HCV-RNA水平最初显著下降（>3 log）的患者在治疗前后进行了NS5A（2209-2248）的序列分析。与治疗前的氨基酸序列相比，这些患者的HCV分离株在治疗后NS5A（2209-2248）区域显示出更多突变。来自欧洲患者的这些发现表明，HCV的NS5A（2209-2248）区域并不代表一个常见的干扰素敏感性决定区域。
