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

机译:T细胞库的胸腺选择对HLA I类相关HIV感染控制的影响

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摘要

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.
机译:如果不进行治疗,大多数感染人类免疫缺陷病毒(HIV)的人最终都会发展为AIDS。罕见的个体(“精英控制者”)未经治疗就保持极低的HIV RNA水平,从而使疾病的发展和传播变得不可能。某些HLA I类等位基因在精英控制者中显着丰富,与HLA-B57的相关性最高(参考文献1)。由于HLA分子具有激活CD8〜+ T细胞的病毒肽,因此免疫介导的机制可能是对HIV更好的控制。在这里,我们描述了HLA-B57分子的肽结合特性如何影响胸腺发育,因此与其他HLA限制性T细胞相比,B57限制性克隆的幼稚库中有较大的一部分可以识别病毒表位,并且这些T细胞对靶向表位的突变体更具交叉反应性。我们的计算预测,这样的T细胞库对免疫优势的HIV表位和紧急突变体施加强大的免疫压力,从而促进了对该病毒的有效控制。为支持这些预测,在大批HLA型个体中,我们的实验表明HLA-B等位基因控制HIV的相对能力与其影响胸腺发育的肽结合特征有关。我们的结果提供了一个概念框架,该框架统一了各种经验性观察,并对疫苗接种策略产生了影响。

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  • 来源
    《Nature》 |2010年第7296期|p.350-354|共5页
  • 作者单位

    Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts 02114, USA Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139,USA;

    Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts 02114, USA Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;

    Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA;

    Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts 02114, USA;

    Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts 02114, USA;

    University of California, San Francisco, California 94110, USA;

    Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts 02114, USA;

    Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts 02114, USA Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA;

    Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts 02114, USA Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA;

    Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts 02114, USA Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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