HIV peptidome-wide association study reveals patient-specific epitope repertoires associated with HIV control
HIV peptidome-wide association study reveals patient-specific epitope repertoires associated with HIV control
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DOI：
10.1073/pnas.1812548116
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发表时间：
2019-01-15
影响因子：
11.1
通讯作者：
Lenz, Tobias L.
中科院分区：
文献类型：
--
作者：
Arora, Jatin;McLare, Paul J.;Lenz, Tobias L.
高度多态的人类白细胞抗原I类分子的多肽结合槽的遗传变异与HIV-1的控制和进展艾滋病有关，占HIV-1设定点病毒载量(SpVL)变异的12%。这表明，HIV-1抗原表位向细胞毒性T细胞呈递在疾病控制中起着关键作用。然而，对相关的人类白细胞抗原结合的HIV表位的全面了解仍然是难以捉摸的。在这里，我们描述了一种多肽组范围的关联研究(Pepwas)方法，该方法集成了来自6,311名HIV感染患者的HLA型和spVL数据，以询问整个HIV-1蛋白质组(3,252个独特的多肽)是否有与疾病相关的多肽。这种Pepwas方法预测了与spVL相关的一组核心表位，包括已知的表位，但也包括几个以前未描述的与疾病相关的多肽。更重要的是，每个患者通过各自的人类白细胞抗原A和B变异体只呈现这些预测的核心表位中的一小部分。最终，这些患者特定表位谱系中的个体差异解释了spVL的变异，这之前与人类白细胞抗原的遗传变异有关。因此，Pepwas能够对人类白细胞抗原和HIV-1控制之间强大但鲜为人知的联系进行全面的功能解释，为靶向治疗的开发确定与疾病相关的表位的简短列表的优先顺序。
Genetic variation in the peptide-binding groove of the highly polymorphic HLA class I molecules has repeatedly been associated with HIV-1 control and progression to AIDS, accounting for up to 12% of the variation in HIV-1 set point viral load (spVL). This suggests a key role in disease control for HLA presentation of HIV-1 epitopes to cytotoxic T cells. However, a comprehensive understanding of the relevant HLA-bound HIV epitopes is still elusive. Here we describe a peptidome-wide association study (PepWAS) approach that integrates HLA genotypes and spVL data from 6,311 HIV-infected patients to interrogate the entire HIV-1 proteome (3,252 unique peptides) for disease-relevant peptides. This PepWAS approach predicts a core set of epitopes associated with spVL, including known epitopes but also several previously uncharacterized disease-relevant peptides. More important, each patient presents only a small subset of these predicted core epitopes through their individual HLA-A and HLA-B variants. Eventually, the individual differences in these patient-specific epitope repertoires account for the variation in spVL that was previously associated with HLA genetic variation. PepWAS thus enables a comprehensive functional interpretation of the robust but little-understood association between HLA and HIV-1 control, prioritizing a short list of disease-associated epitopes for the development of targeted therapy.