Department of Microbiology and Immunology, University of Melbourne, Parkville, VIC 3010, Australia.
Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5570-5. doi: 10.1073/pnas.1302935110. Epub 2013 Mar 14.
A reverse-genetics approach has been used to probe the mechanism underlying immune escape for influenza A virus-specific CD8(+) T cells responding to the immunodominant D(b)NP366 epitope. Engineered viruses with a substitution at a critical residue (position 6, P6M) all evaded recognition by WT D(b)NP366-specific CD8(+) T cells, but only the NPM6I and NPM6T mutants altered the topography of a key residue (His155) in the MHC class I binding site. Following infection with the engineered NPM6I and NPM6T influenza viruses, both mutations were associated with a substantial "hole" in the naïve T-cell receptor repertoire, characterized by very limited T-cell receptor diversity and minimal primary responses to the NPM6I and NPM6T epitopes. Surprisingly, following respiratory challenge with a serologically distinct influenza virus carrying the same mutation, preemptive immunization against these escape variants led to the generation of secondary CD8(+) T-cell responses that were comparable in magnitude to those found for the WT NP epitope. Consequently, it might be possible to generate broadly protective T-cell immunity against commonly occurring virus escape mutants. If this is generally true for RNA viruses (like HIV, hepatitis C virus, and influenza) that show high mutation rates, priming against predicted mutants before an initial encounter could function to prevent the emergence of escape variants in infected hosts. That process could be a step toward preserving immune control of particularly persistent RNA viruses and may be worth considering for future vaccine strategies.
一种反向遗传学方法被用于探究流感病毒 A 特异性 CD8(+) T 细胞对免疫显性 D(b)NP366 表位的免疫逃逸机制。在关键残基（位置 6，P6M）处发生取代的工程化病毒均能逃避 WT D(b)NP366 特异性 CD8(+) T 细胞的识别，但只有 NPM6I 和 NPM6T 突变改变了 MHC Ⅰ结合位点中关键残基（His155）的拓扑结构。感染工程化的 NPM6I 和 NPM6T 流感病毒后，这两种突变都与幼稚 T 细胞受体库中出现明显的“空洞”相关，其特征是 T 细胞受体多样性非常有限，对 NPM6I 和 NPM6T 表位的初级反应极小。令人惊讶的是，在与携带相同突变的血清学上不同的流感病毒进行呼吸道挑战后，针对这些逃逸变体的抢先免疫会引发继发性 CD8(+) T 细胞反应，其规模与针对 WT NP 表位的反应相当。因此，有可能针对常见的病毒逃逸突变体产生广泛保护性的 T 细胞免疫。如果这对于具有高突变率的 RNA 病毒（如 HIV、丙型肝炎病毒和流感病毒）普遍如此，那么在初次接触之前针对预测的突变体进行免疫接种，可能有助于防止感染宿主中逃逸变体的出现。这个过程可能是保持对特别持久的 RNA 病毒的免疫控制的一步，可能值得考虑用于未来的疫苗策略。
