Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.
J Virol. 2011 Nov;85(22):11883-90. doi: 10.1128/JVI.00779-11. Epub 2011 Aug 31.
While human leukocyte antigen B57 (HLA-B57) is associated with the spontaneous clearance of hepatitis C virus (HCV), the mechanisms behind this control remain unclear. Immunodominant CD8(+) T cell responses against the B57-restricted epitopes comprised of residues 2629 to 2637 of nonstructural protein 5B (NS5B(2629-2637)) (KSKKTPMGF) and E2(541-549) (NTRPPLGNW) were recently shown to be crucial in the control of HCV infection. Here, we investigated whether the selection of deleterious cytotoxic T lymphocyte (CTL) escape mutations in the NS5B KSKKTPMGF epitope might impair viral replication and contribute to the B57-mediated control of HCV. Common CTL escape mutations in this epitope were identified from a cohort of 374 HCV genotype 1a-infected subjects, and their impact on HCV replication assessed using a transient HCV replicon system. We demonstrate that while escape mutations at residue 2633 (position 5) of the epitope had little or no impact on HCV replication in vitro, mutations at residue 2629 (position 1) substantially impaired replication. Notably, the deleterious mutations at position 2629 were tightly linked in vivo to upstream mutations at residue 2626, which functioned to restore the replicative defects imparted by the deleterious escape mutations. These data suggest that the selection of costly escape mutations within the immunodominant NS5B KSKKTPMGF epitope may contribute in part to the control of HCV replication in B57-positive individuals and that persistence of HCV in B57-positive individuals may involve the development of specific secondary compensatory mutations. These findings are reminiscent of the selection of deleterious CTL escape and compensatory mutations by HLA-B57 in HIV-1 infection and, thus, may suggest a common mechanism by which alleles like HLA-B57 mediate protection against these highly variable pathogens.
虽然人类白细胞抗原 B57（HLA-B57）与丙型肝炎病毒（HCV）的自发清除有关，但这种控制背后的机制仍不清楚。最近的研究表明，针对非结构蛋白 5B（NS5B）（2629 至 2637 位氨基酸残基）（KSKKTPMGF）和 E2（541-549）（NTRPPLGNW）的 B57 限制性表位的免疫优势 CD8(+)T 细胞反应在 HCV 感染的控制中至关重要。在这里，我们研究了 NS5B KSKKTPMGF 表位中有害细胞毒性 T 淋巴细胞（CTL）逃逸突变的选择是否可能损害病毒复制并有助于 B57 介导的 HCV 控制。从 374 名 HCV 基因型 1a 感染患者队列中鉴定了该表位中的常见 CTL 逃逸突变，并使用瞬时 HCV 复制子系统评估其对 HCV 复制的影响。我们证明，尽管表位 2633 位（第 5 位）的逃逸突变对体外 HCV 复制几乎没有影响，但 2629 位（第 1 位）的突变则显著损害了复制。值得注意的是，体内位置 2629 的有害突变与位置 2626 的上游突变紧密相关，这些突变恢复了有害逃逸突变所带来的复制缺陷。这些数据表明，免疫优势 NS5B KSKKTPMGF 表位内选择代价高昂的逃逸突变可能部分有助于 B57 阳性个体中 HCV 复制的控制，并且 B57 阳性个体中 HCV 的持续存在可能涉及特定的继发性补偿性突变的发展。这些发现让人联想到 HLA-B57 在 HIV-1 感染中选择有害 CTL 逃逸和补偿性突变的情况，因此可能表明像 HLA-B57 这样的等位基因介导对这些高度变异病原体的保护的共同机制。
