T细胞的胸腺选择在HLAI类抗原对于HIV感染的作用

【摘要】如果未经治疗，大多数感染了人类免疫缺陷病毒（HIV）者最终进展为爱滋病患者。罕见个人（'精英控制者'）在未经治疗时维持艾滋病毒RNA在非常低的水平，从而使疾病恶化和传染的可能性不大。某些人类白细胞抗原I类等位基因在精英控制者富集，和检测到的HLA-B57最有相关性。由于HLA分子呈递病毒多肽，激活CD8 + T细胞，这是一种监控HIV的免疫介导机制。在这里，我们描述HLA - B57分子的多肽结合特性如何影响胸腺的发展，如此，相对于其他HLA限制性T细胞，在B57的限制克隆较大部分能确认病毒抗原的表位，这些T细胞对于抗原决定簇突变表位有更多的交叉反应。我们的计算预测，这种T细胞对于免疫优势的艾滋病毒抗原表位和急变株具有强大的免疫力，从而加强对病毒的有效控制。支持在一个大的队列这些预言，一个大型的人类白细胞抗原类型的个人队列研究支持这些预测，我们的实验表明人类白细胞抗原- B控制艾滋病毒的能力和它们肽结合的特性有关，这些特性影响胸腺发展。我们的结果提供一个概念框架，统一了不同的观察经验，并对疫苗接种策略具有影响。

原文：

Effects of thymic selection of the T-cell repertoire on HLA classI-associated
control of HIV infection

【Abstract】Without therapy, most people infected with human immunodeficiency virus (HIV) ultimately progress to AIDS. Rare individuals (‘elite controllers’) maintain very low levels of HIV RNA without therapy, thereby making disease progression and transmission unlikely. Certain HLA class I alleles are markedly enriched in elite controllers, with the highest association observed for HLA-B57 (ref. 1). Because HLA molecules present viral peptides that activate CD8+ T cells, an immune-mediated mechanism is probably responsible for superior control of HIV. Here we describe how the peptide-binding characteristics of HLA-B57 molecules affect thymic development such that, compared to other HLA-restricted T cells, a larger fraction of the naive repertoire of B57-restricted clones recognizes a viral epitope, and these T cells are more cross-reactive to mutants of targeted epitopes. Our calculations predict that such a T-cell repertoire imposes strong immune pressure on immunodominant HIV epitopes and emergent mutants, thereby promoting efficient control of the virus. Supporting these predictions, in a large cohort of HLA-typed individuals, our experiments show that the relative ability of HLA-B alleles to control HIV correlates with their peptide-binding characteristics that affect thymic development. Our results provide a conceptual framework that unifies diverse empirical observations, and have implications for vaccination strategies.

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