Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Izumi N, Marumo F, Sato C
Second Department of Internal Medicine, Faculty of Medicine, Tokyo Medical and Dental University, Japan.
J Clin Invest. 1995 Jul;96(1):224-30. doi: 10.1172/JCI118025.
We have previously demonstrated that sensitivity to interferon is different among hepatitis C virus (HCV) quasispecies simultaneously detected in same individuals and that interferon-resistant HCV quasispecies are selected during the treatment. To determine the genetic basis of their resistance to interferon, HCV genotype-1b was obtained from serum of three patients before and during interferon therapy, and their full-length nucleotide and deduced amino acid sequences were determined. Comparison of the pairs of interferon-resistant and interferon-sensitive HCV isolates in respective individuals demonstrated clusters of amino acid differences in the COOH-terminal half of the NS5A region (codon 2154-2383), which contained a common unique amino acid difference at codon 2218. Additional sequence data of the COOH-terminal half of the NS5A region obtained from six interferon-resistant and nine interferon-sensitive HCV confirmed the exclusive existence of missense mutations in a 40 amino acid stretch of the NS5A region around codon 2218 (from codon 2209 to 2248) in interferon-sensitive HCV. On the other hand, this region of interferon-resistant HCV was identical to that of prototype HCV genotype-1b (HCV-J, HCV-JTa, or HC-J4). We designated this region as the interferon sensitivity determining region. Thus, HCV genotype-1b with the prototype interferon sensitivity determining region appears to be interferon-resistant strains. The specific nature of these mutations might make it possible to predict prognostic effects of interferon treatment.
我们之前已经证明，在同一患者体内同时检测到的丙型肝炎病毒（HCV）准种对干扰素的敏感性不同，且在治疗过程中会选择出对干扰素耐药的HCV准种。为了确定它们对干扰素耐药的遗传基础，在干扰素治疗前和治疗期间从三名患者的血清中获取了HCV 1b基因型，并测定了其全长核苷酸序列和推导的氨基酸序列。对各患者中对干扰素耐药和敏感的HCV分离株进行比较，结果显示在NS5A区域的COOH末端一半（密码子2154 - 2383）存在氨基酸差异簇，其中在密码子2218处存在一个共同的独特氨基酸差异。从六个对干扰素耐药和九个对干扰素敏感的HCV中获得的NS5A区域COOH末端一半的额外序列数据证实，在干扰素敏感的HCV中，围绕密码子2218（从密码子2209至2248）的NS5A区域的40个氨基酸片段中存在错义突变。另一方面，对干扰素耐药的HCV的该区域与HCV 1b基因型原型（HCV-J、HCV-JTa或HC-J4）相同。我们将该区域指定为干扰素敏感性决定区域。因此，具有原型干扰素敏感性决定区域的HCV 1b基因型似乎是干扰素耐药株。这些突变的特异性可能使得预测干扰素治疗的预后效果成为可能。
