Fitness costs limit viral escape from cytotoxic T lymphocytes at a structurally constrained epitope
Fitness costs limit viral escape from cytotoxic T lymphocytes at a structurally constrained epitope
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DOI：
10.1128/jvi.78.24.13901-13910.2004
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发表时间：
2004-12-01
影响因子：
5.4
通讯作者：
Letvin, NL
中科院分区：
文献类型：
--
作者：
Peyerl, FW;Bazick, HS;Letvin, NL
病毒特异性细胞毒性T淋巴细胞(CTL)对复制人类免疫缺陷病毒和猴免疫缺陷病毒施加强烈的选择压力，导致CTL表位突变的积累。人们一直认为，适合性成本可以限制CTL表位突变的进化。然而，只有有限数量的研究仔细研究了这种可能性。为了探索与病毒逃避p11C，C-M特异性CTL相关的适应成本，我们构建了一组病毒，编码整个p11C，C-M表位每个位置的点突变。表位第3、4、5、6、7和9位的氨基酸替换通过改变病毒产量和Gag蛋白表达以及破坏成熟核心的稳定而显著削弱病毒复制。抗原表位第2位的氨基酸替换是可以容忍的，但需要逆转或额外的补偿性突变才能产生复制能力强的病毒。最后，虽然p11C，C-M表位第1位和第8位的氨基酸替换在功能上是耐受的，但这些替换被p11C，C-M特异性CTL识别，因此没有为病毒提供选择优势。综上所述，这些数据表明编码p11C，C-M表位的衣壳区域可以容忍有限的序列变异，因此只有非常有限的突变才能成功地使病毒逃脱p11C，C-M特异性的CTL反应。
The intense selection pressure exerted by virus-specific cytotoxic T lymphocytes (CTL) on replicating human immunodeficiency virus and simian immunodeficiency virus results in the accumulation of CTL epitope mutations. It has been assumed that fitness costs can limit the evolution of CTL epitope mutations. However, only a limited number of studies have carefully examined this possibility. To explore the fitness costs associated with viral escape from p11C, C-M-specific CTL, we constructed a panel of viruses encoding point mutations at each position of the entire p11C, C-M epitope. Amino acid substitutions at positions 3, 4, 5, 6, 7, and 9 of the epitope significantly impaired virus replication by altering virus production and Gag protein expression as well as by destabilizing mature cores. Amino acid substitutions at position 2 of the epitope were tolerated but required reversion or additional compensatory mutations to generate replication-competent viruses. Finally, while amino acid substitutions at positions 1 and 8 of the p11C, C-M epitope were functionally tolerated, these substitutions were recognized by p11C, C-M-specific CTL and therefore provided no selection advantage for the virus. Together, these data suggest that limited sequence variation is tolerated by the region of the capsid encoding the p11C, C-M epitope and therefore that only a very limited number of mutations can allow successful viral escape from the p11C, C-M-specific CTL response.