Human Leukocyte Antigen B27 Selects for Rare Escape Mutations That Significantly Impair Hepatitis C Virus Replication and Require Compensatory Mutations
Human Leukocyte Antigen B27 Selects for Rare Escape Mutations That Significantly Impair Hepatitis C Virus Replication and Require Compensatory Mutations
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DOI：
10.1002/hep.24541
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发表时间：
2011-10-01
期刊：
影响因子：
13.5
通讯作者：
Allen, Todd M.
中科院分区：
文献类型：
--
作者：
Neumann-Haefelin, Christoph;Oniangue-Ndza, Cesar;Allen, Todd M.
人类白细胞抗原B27与丙型肝炎病毒（HCV）感染中的病毒自发清除相关。免疫显性、HLA-B27限制性、HCV特异性、分化簇（CD）8（+）T细胞表位、非结构蛋白（NS）5 B（2841-2849）（ARMILMTHF）内的病毒逃逸已被证明受到病毒适应性成本以及广泛的T细胞交叉识别的限制，表明HLA-B27的潜在保护机制。在这里，我们研究了亚显性HLA-B27限制性表位，NS 5 B（2936-2944）（GRAAICGKY），以进一步确定HLA-B27的保护机制。我们在一个大的HCV基因型1a感染的患者队列中发现了该表位内独特的逃逸突变模式。在亚基因组HCV复制子系统中评估，主要逃逸突变代表HLA-B27主要锚残基或T细胞受体接触位点的保守取代，这两者都不损害病毒复制能力。然而，相反，在HLA-B27（+）受试者的一个子集中，HLA-B27锚残基R（2937）出现罕见的逃逸突变，几乎消除了病毒复制。值得注意的是，这些罕见的突变只发生在两个同样罕见的，结构上接近的上游突变的选择。这些上游突变与罕见的逃逸突变的共表达显着恢复病毒复制能力从= 70%的野生型水平。结论：在HLA-B27限制性表位中选择罕见的CTL逃逸突变会显著损害病毒的复制适应性，除非得到适当的补偿。这些数据支持HLA-B27靶向高度限制区域的作用，其能够断言对HCV和其他高度可变病原体的免疫控制。（肝脏学2011;54：1157-1166）
Human leukocyte antigen B27 is associated with spontaneous viral clearance in hepatitis C virus (HCV) infection. Viral escape within the immunodominant, HLA-B27-restricted, HCV-specific, cluster of differentiation (CD)8(+) T-cell epitope, nonstructural protein (NS)5B(2841-2849) (ARMILMTHF), has been shown to be limited by viral fitness costs as well as broad T-cell cross-recognition, suggesting a potential mechanism of protection by HLA-B27. Here, we studied the subdominant HLA-B27-restricted epitope, NS5B(2936-2944) (GRAAICGKY), to further define the mechanisms of protection by HLA-B27. We identified a unique pattern of escape mutations within this epitope in a large cohort of HCV genotype 1a-infected patients. The predominant escape mutations represented conservative substitutions at the main HLA-B27 anchor residue or a T-cell receptor contact site, neither of which impaired viral replication capacity, as assessed in a subgenomic HCV replicon system. In contrast, however, in a subset of HLA-B27(+) subjects, rare escape mutations arose at the HLA-B27 anchor residue, R(2937), which nearly abolished viral replication. Notably, these rare mutations only occurred in conjunction with the selection of two equally rare, and structurally proximal, upstream mutations. Coexpression of these upstream mutations with the rare escape mutations dramatically restored viral replication capacity from = 70% of wild-type levels. Conclusion: The selection of rare CTL escape mutations in this HLA-B27-restricted epitope dramatically impairs viral replicative fitness, unless properly compensated. These data support a role for the targeting of highly constrained regions by HLA-B27 in its ability to assert immune control of HCV and other highly variable pathogens. (HEPATOLOGY 2011;54:1157-1166)