Fundacio irsiCaixa, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain.
J Virol. 2011 Jun;85(12):5961-9. doi: 10.1128/JVI.00308-11. Epub 2011 Apr 6.
The role of the hepatitis C virus (HCV) NS3/4A protease in ablating the signaling pathway involved in the production of alpha/beta interferon (IFN-α/β) suggests a relationship between NS3/4A proteolytic activity and a patient's response to IFN-based therapy. To identify viral factors associated with the HCV treatment response, we analyzed the pretreatment NS3/4A protease gene quasispecies composition of 56 HCV genotype 1-HIV-1-coinfected patients treated in our clinic with pegylated IFN (pegIFN) plus ribavirin (RBV). The catalytic efficiency of the dominant (i.e., the most abundant) quasispecies was also assayed for Cardif cleavage and correlated with treatment outcome. A total of 1,745 clones were isolated and sequenced. Significantly less nucleotide quasispecies heterogeneity and lower Shannon entropy values were detected within the responder group (P < 0.05). A correlation was also found between the efficiency of NS3/4A protease Cardif cleavage and therapy outcome. Proteases from sustained responder patients were more efficient at processing Cardif (mean ± standard error of the mean [SEM], 0.8960 ± 0.05568; n = 19) than proteases from nonresponders (mean ± SEM, 0.7269 ± 0.05306; n = 37; P < 0.05). Finally, the amino acid p distance (the proportion [p] of nucleotide sites at which two sequences being compared are different) was significantly shorter in patients with an interleukin-28B (IL-28B) risk allele (P < 0.01), suggesting that IL-28B risk allele carriers exert a lower positive selection pressure on the NS3/4A protease. NS3/4A protease efficiency in cleaving Cardif may be associated with the pegIFN-RBV treatment response, as shown in our cohort of HIV-HCV-coinfected patients. Greater NS3/4A nucleotide heterogeneity and higher Shannon entropy values in nonresponders suggest that less HCV quasispecies complexity may favor a better response to pegIFN-RBV.
丙型肝炎病毒 (HCV) NS3/4A 蛋白酶在消除涉及α/β干扰素 (IFN-α/β) 产生的信号通路中的作用表明 NS3/4A 蛋白水解活性与患者对 IFN 为基础的治疗的反应之间存在关系。为了确定与 HCV 治疗反应相关的病毒因素，我们分析了在我们诊所接受聚乙二醇化 IFN (pegIFN) 加利巴韦林 (RBV) 治疗的 56 名 HCV 基因型 1-HIV-1 合并感染患者的预处理 NS3/4A 蛋白酶基因准种组成。还测定了主要（即最丰富）准种的催化效率，并与治疗结果相关联。共分离和测序了 1745 个克隆。在应答组中检测到核苷酸准种异质性明显减少，香农熵值降低 (P < 0.05)。还发现 NS3/4A 蛋白酶 Cardif 切割的效率与治疗结果之间存在相关性。持续应答者患者的蛋白酶在加工 Cardif 方面效率更高（平均值 ± 标准误 [SEM]，0.8960 ± 0.05568；n = 19）比无应答者（平均值 ± SEM，0.7269 ± 0.05306；n = 37；P < 0.05）。最后，在具有白细胞介素-28B (IL-28B) 风险等位基因的患者中，氨基酸 p 距离（比较的两个序列中核苷酸位点不同的比例 [p]）明显缩短（P < 0.01），表明 IL-28B 风险等位基因携带者对 NS3/4A 蛋白酶施加的正向选择压力较低。在我们的 HIV-HCV 合并感染患者队列中，Cardif 切割的 NS3/4A 蛋白酶效率可能与 pegIFN-RBV 治疗反应相关。非应答者的 NS3/4A 核苷酸异质性更大，香农熵值更高，表明 HCV 准种复杂性降低可能更有利于 pegIFN-RBV 的治疗反应。
