Gerotto M, Dal Pero F, Sullivan D G, Chemello L, Cavalletto L, Polyak S J, Pontisso P, Gretch D R, Alberti A
Department of Clinical and Experimental Medicine, University of Padua, Italy.
J Viral Hepat. 1999 Sep;6(5):367-72. doi: 10.1046/j.1365-2893.1999.00166.x.
Resistance of the hepatitis C virus (HCV) to interferon-alpha (IFN-alpha) therapy in patients with hepatitis C may be genetically controlled by an IFN sensitivity-determining region (ISDR) within the non-structural 5A (NS5A) gene. To assess whether HCV 1b strains carrying a 'resistant' type of ISDR are selected during unsuccessful IFN therapy, we analysed the evolution of the NS5A quasispecies, as detected by the clonal frequency analysis technique, and of the ISDR sequence by nucleotide sequence determination, in 11 patients showing no virological response during two consecutive cycles of IFN-alpha therapy. IFN-resistant patients had a homogeneous ISDR quasispecies with sequences identical to those described as 'resistant-' or 'intermediate-' type ISDR. After retreatment with IFN, further selection towards a homogeneous viral population was observed and 10 out of 11 patients had only one variant of HCV with no or just one single amino acid mutation within the ISDR sequence. Treatment and retreatment with IFN was associated in our non-responder patients with evolution of the ISDR quasispecies towards a rather homogeneous viral population carrying a conserved or minimally mutated ISDR motif, supporting the idea that this motif may be relevant for IFN resistance in HCV 1b-infected individuals.
丙型肝炎患者中丙型肝炎病毒（HCV）对α干扰素（IFN-α）治疗的耐药性可能由非结构5A（NS5A）基因内的IFN敏感性决定区域（ISDR）进行基因控制。为了评估在IFN治疗失败期间是否会选择携带“耐药”型ISDR的HCV 1b毒株，我们通过克隆频率分析技术检测了11例在两个连续IFN-α治疗周期中未出现病毒学应答的患者的NS5A准种的演变情况，并通过核苷酸序列测定分析了ISDR序列。对IFN耐药的患者具有均一的ISDR准种，其序列与被描述为“耐药”或“中间”型ISDR的序列相同。在用IFN再次治疗后，观察到进一步向均一病毒群体的选择，并且11例患者中有l0例仅有一种HCV变体，其ISDR序列中没有或仅有一个单氨基酸突变。在我们的无应答患者中，IFN治疗和再次治疗与ISDR准种向携带保守或最小突变ISDR基序的相当均一的病毒群体演变有关，这支持了该基序可能与HCV 1b感染个体中的IFN耐药性相关的观点。
