Lu M, Wiese M, Roggendorf M
Institut für Virologie, Universitätsklinikun Essen, Essen, Germany.
J Med Virol. 1999 Oct;59(2):146-53. doi: 10.1002/(sici)1096-9071(199910)59:2<146::aid-jmv4>3.0.co;2-o.
Interferon alpha (IFN alpha) can suppress the replication of hepatitis C virus (HCV) in chronically infected patients. However, HCV persists in a significant number of patients despite the normalization of alanine transaminase (ALT) during IFN alpha therapy. In this study, HCV variants in patients under IFN alpha therapy were characterized to examine their role in viral persistence during the therapy. Sixteen patients selected for this study were infected with HCV genotype 1b and remained HCV RNA positive for at least 1 month after onset of therapy. Nine patients responded to the therapy in terms of normalization of ALT (responders), whereas seven patients did not show a significant decrease of ALT level (nonresponders). To examine HCV populations in these patients, the HCV 5' noncoding region (5' NCR) was analyzed by polymerase chain reaction amplification and sequencing. Newly emerging variants of the HCV 5' NCR replaced predominant variants present prior to IFN alpha therapy in six of nine responders. Most predominant HCV variants during IFN alpha therapy carried a nucleotide substitution G to A at nt 231 within the 5' NCR. An analysis of the HCV quasispecies population in one responder revealed that a preexisting variant became predominant under IFN alpha therapy. These results emphasized the importance of the genetic heterogeneity of the HCV genome for viral resistance to IFN alpha. Five of seven HCV isolates from nonresponders were identical to those found in responders with regard to the nucleotide sequence of the 5' NCR. However, no selection of variants of the HCV 5' NCR occurred in nonresponders during the course of therapy. We conclude that IFN alpha treatment leads to the selection of variants of the HCV 5' NCR only in responders and may act differently in nonresponders. Our results suggest that the HCV 5' NCR may be a target of anti-HCV actions of IFN alpha.
α干扰素（IFNα）可抑制慢性感染患者体内丙型肝炎病毒（HCV）的复制。然而，尽管在IFNα治疗期间丙氨酸转氨酶（ALT）恢复正常，但仍有相当数量的患者体内HCV持续存在。在本研究中，对接受IFNα治疗的患者体内的HCV变异体进行了特征分析，以研究它们在治疗期间病毒持续存在中的作用。本研究选取的16例患者感染了HCV 1b基因型，且在治疗开始后至少1个月内HCV RNA仍呈阳性。9例患者的ALT恢复正常（应答者），而7例患者的ALT水平未显著下降（无应答者）。为检测这些患者体内的HCV群体，通过聚合酶链反应扩增和测序分析了HCV 5'非编码区（5' NCR）。在9例应答者中的6例中，IFNα治疗后新出现的HCV 5' NCR变异体取代了治疗前存在的主要变异体。IFNα治疗期间大多数主要的HCV变异体在5' NCR的第231位核苷酸处发生了从G到A的替换。对1例应答者体内HCV准种群体的分析显示，一种预先存在的变异体在IFNα治疗下成为主要变异体。这些结果强调了HCV基因组遗传异质性对病毒对IFNα耐药性的重要性。7例无应答者的HCV分离株中有5例在5' NCR核苷酸序列方面与应答者中发现的相同。然而，在治疗过程中无应答者体内未发生HCV 5' NCR变异体的选择。我们得出结论，IFNα治疗仅在应答者中导致HCV 5' NCR变异体的选择，且在无应答者中的作用可能不同。我们的结果表明，HCV 5' NCR可能是IFNα抗HCV作用的靶点。
