Functional properties and epitope characteristics of T-cells recognizing natural HIV-1 variants.
Functional properties and epitope characteristics of T-cells recognizing natural HIV-1 variants.
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T 细胞识别天然 HIV-1 变异体的功能特性和表位特征。
DOI：
10.1016/j.vaccine.2009.08.093
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发表时间：
2009
期刊：
影响因子：
5.5
通讯作者：
McElrath,MJ
中科院分区：
文献类型：
--
作者：
Malhotra,U;Nolin,J;Horton,H;Li,F;Corey,L;Mullins,JI;McElrath,MJ
为了了解如何实现对HIV-1变体的广泛识别，我们检查了新感染者以及疫苗接受者对含有保守、半保守和非保守氨基酸取代的广谱潜在T细胞表位（PTE）变体的T细胞反应性。在早期感染者中，T细胞识别具有一个取代的表位变体的频率显著高于具有两个（P=0.0098）和三个（P=0.0125）取代的表位变体。此外，T细胞识别含有保守置换的变体的频率高于含有半保守（P=0.0029）和非保守（P<0.0001）置换的变体。通过疫苗诱导的T细胞对变体的识别观察到类似的效果。此外，即使当识别出变体时，IFN-γ和颗粒酶B应答以及T细胞增殖的幅度也较低。最后，我们表明，表位分布的加工偏好和氨基酸熵的强烈影响。我们的结论是，诱导广泛的免疫可能需要免疫原序列，包括多种变体。然而，基于肽和序列的疫苗免疫原的成本有效的设计，提供最大的循环序列的覆盖率可以通过强调可能是T细胞靶的病毒结构域来实现。
To understand how broad recognition of HIV-1 variants may be achieved we examined T-cell reactivity in newly infected persons as well as vaccine recipients to a broad spectrum of potential T-cell epitope (PTE) variants containing conservative, semi-conservative and non-conservative amino acid substitutions. Among early infected persons T-cells recognized epitope variants with one substitution at a significantly higher frequency versus those with two (P=0.0098) and three (P=0.0125) substitutions. Furthermore T-cells recognized variants containing conservative substitutions at a higher frequency versus those containing semi-conservative (P=0.0029) and non-conservative (P<0.0001) substitutions. Similar effects were observed on recognition of variants by vaccine-induced T-cells. Moreover even when variants were recognized, the IFN-γ and granzyme B responses as well as T-cell proliferation were of lower magnitude. Finally, we show that epitope distribution is strongly influenced by both processing preferences and amino acid entropy. We conclude that induction of broad immunity is likely to require immunogen sequences that encompass multiple variants. However, cost-effective design of peptide and sequence based vaccine immunogens that provide maximal coverage of circulating sequences may be achieved through emphasis on virus domains likely to be T-cell targets.