Functional consequences of human immunodeficiency virus escape from an HLA-B*13-restricted CD8+ T-cell epitope in p1 Gag protein.
Functional consequences of human immunodeficiency virus escape from an HLA-B*13-restricted CD8+ T-cell epitope in p1 Gag protein.
复制标题
人类免疫缺陷病毒逃离 p1 Gag 蛋白中 HLA-B*13 限制性 CD8 T 细胞表位的功能后果。
DOI：
10.1128/jvi.01882-08
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发表时间：
2009
影响因子：
5.4
通讯作者：
Prado JG
中科院分区：
文献类型：
--
作者：
Prado JG
HLA-B*13与人类免疫缺陷病毒1型（HIV-1）感染控制之间的相关性已被证实与Gag特异性HLA-B*13限制性细胞毒性T细胞（CTL）应答的数量有关。迄今为止，所描述的导致病毒的体外适应性成本的Gag逃逸突变仅位于结构蛋白p24内。在这里，我们研究了这样一种假设，即HIV Gag其他区域内的CTL逃逸突变也可能降低病毒适应性并有助于免疫控制。我们分析了HLA-B*13限制性CTL对p1 Gag中表位RQANFLGKI 429 -437（RI 9）的应答，其中Gag残基436和437处的氨基酸变异与HLA-B*13表达相关。在这项工作中，我们评估了这些位置上的氨基酸取代对CTL识别和HIV-1适应性的影响。我们证明，取代I437 L和I437 M在很大程度上废除了CTL识别和降低病毒适应性，而变体K436 R和I437 V对识别和适应性仅具有边际效应。蛋白质合成模式的检查表明，I437 L和I437 M突变体中的适应性丧失与未加工的Gag前体的积累有关。用I437 M观察到核糖体移码效率的显著降低，表明该机制有助于观察到的该病毒的适应性降低。这些研究说明了在p1 Gag中CTL识别的逃避和病毒适应性的功能后果之间对病毒可用的明显权衡。
The observed association between HLA-B*13 and control of human immunodeficiency virus type 1 (HIV-1) infection has been linked to the number of Gag-specific HLA-B*13-restricted cytotoxic T-cell (CTL) responses identified. To date, the Gag escape mutations described that result in an in vitro fitness cost to the virus have been located within structural protein p24 only. Here we investigated the hypothesis that CTL escape mutations within other regions of HIV Gag may also reduce viral fitness and contribute to immune control. We analyzed an HLA-B*13-restricted CTL response toward an epitope in p1 Gag, RQANFLGKI429-437(RI9), where amino acid variation at Gag residues 436 and 437 is associated with HLA-B*13 expression. In this work, we assessed the impact of amino acid substitutions at these positions on CTL recognition and on HIV-1 fitness. We demonstrated that substitutions I437L and I437M largely abrogate CTL recognition and reduce viral fitness while variants K436R and I437V have only a marginal effect on recognition and fitness. Examination of the patterns of protein synthesis indicated that the loss of fitness in the I437L and I437M mutants is associated with the accumulation of unprocessed Gag precursors. A significant reduction in ribosomal frameshifting efficiency was observed with I437M, suggesting that this mechanism contributes to the observed reduced fitness of this virus. These studies illustrate the apparent trade-off available to the virus between evasion of CTL recognition in p1 Gag and the functional consequences for viral fitness.