Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
J Virol. 2012 Nov;86(21):11493-500. doi: 10.1128/JVI.01020-12. Epub 2012 Aug 15.
Genetic variation within the HLA-B locus has the strongest impact on HIV disease progression of any polymorphisms within the human genome. However, identifying the exact mechanism involved is complicated by several factors. HLA-Bw4 alleles provide ligands for NK cells and for CD8 T cells, and strong linkage disequilibrium between HLA class I alleles complicates the discrimination of individual HLA allelic effects from those of other HLA and non-HLA alleles on the same haplotype. Here, we exploit an experiment of nature involving two recently diverged HLA alleles, HLA-B42:01 and HLA-B42:02, which differ by only a single amino acid. Crucially, they occur primarily on identical HLA class I haplotypes and, as Bw6 alleles, do not act as NK cell ligands and are therefore largely unconfounded by other genetic factors. We show that in an outbred cohort (n = 2,093) of HIV C-clade-infected individuals, a single amino acid change at position 9 of the HLA-B molecule critically affects peptide binding and significantly alters the cytotoxic T lymphocyte (CTL) epitopes targeted, measured directly ex vivo by gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay (P = 2 × 10(-10)) and functionally through CTL escape mutation (P = 2 × 10(-8)). HLA-B42:01, which presents multiple Gag epitopes, is associated with a 0.52 log(10) lower viral-load set point than HLA-B42:02 (P = 0.02), which presents no p24 Gag epitopes. The magnitude of this effect from a single amino acid difference in the HLA-A30:01/B42/Cw17:01 haplotype is equivalent to 75% of that of HLA-B57:03, the most protective HLA class I allele in this population. This naturally controlled experiment represents perhaps the clearest demonstration of the direct impact of a particular HIV-specific CTL on disease control.
人类基因组中，HLA-B 基因座内的遗传变异对 HIV 疾病进展的影响最大。然而，确定确切的机制很复杂，因为有几个因素。HLA-Bw4 等位基因为 NK 细胞和 CD8 T 细胞提供配体，而 HLA Ⅰ类等位基因之间的强连锁不平衡使区分同一单倍型上的个别 HLA 等位基因效应与其他 HLA 和非 HLA 等位基因的效应变得复杂。在这里，我们利用涉及两个最近分化的 HLA 等位基因 HLA-B42:01 和 HLA-B42:02 的自然实验，它们仅在一个氨基酸上有所不同。至关重要的是，它们主要存在于相同的 HLA Ⅰ类单倍型上，并且作为 Bw6 等位基因，它们不是 NK 细胞的配体，因此受其他遗传因素的影响较小。我们表明，在一个由 HIV C 型感染个体组成的异质群体（n = 2093）中，HLA 分子第 9 位的一个氨基酸变化对肽结合具有重要影响，并显著改变了细胞毒性 T 淋巴细胞（CTL）的表位，这些表位是通过直接的 IFN-γ酶联免疫斑点（ELISPOT）试验（P = 2×10(-10)) 进行体外测量的，并且通过 CTL 逃逸突变进行功能测量（P = 2×10(-8))。与 HLA-B42:02 相比，HLA-B42:01 呈现多个 Gag 表位，其病毒载量设定点低 0.52log10（P = 0.02），而 HLA-B42:02 则没有 p24 Gag 表位。在 HLA-A30:01/B42/Cw17:01 单倍型中单个氨基酸差异的影响大小与该人群中最具保护性的 HLA Ⅰ类等位基因 HLA-B*57:03 的影响相当，为 75%。这个自然控制的实验代表了 HIV 特异性 CTL 对疾病控制的直接影响的最清晰证明。
