TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection.
TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection.
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DOI：
10.1038/ni.2342
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发表时间：
2012-06-10
影响因子：
30.5
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人类白细胞抗原（HLA） B*27和B*57与预防HIV-1疾病进展有关，但大多数表达这些等位基因的人无法控制HIV-1。在这里，我们发现控制者和进展者中的HLA-B*27限制性CD8+ T细胞通过靶向免疫优势Gag表位来抑制病毒复制的能力不同。这与不同的TCR克隆型有关，其特点是体外对HIV-1复制的良好控制，对表位变异的交叉反应性更强，穿孔蛋白递送增强。在控制者和进展者中，也观察到免疫显性HLA-B*57限制性反应的克隆型特异性抗病毒疗效差异。因此，保护性等位基因的功效受到自然感染中选择的特定TCR克隆型的调节，为不同的HIV-1结果提供了功能上的解释。
Human leukocyte antigen (HLA) B*27 and B*57 are associated with protection against HIV-1 disease progression, yet most persons expressing these alleles are unable to control HIV-1. Here we show that HLA-B*27-restricted CD8+ T cells in controllers and progressors differ in their ability to inhibit virus replication through targeting of the immunodominant Gag epitope. This is associated with distinct TCR clonotypes, characterized by superior control of HIV-1 replication in vitro, greater cross-reactivity against epitope variants, and enhanced perforin delivery. Clonotype-specific differences in antiviral efficacy were also observed for an immunodominant HLA-B*57 restricted response in controllers and progressors. Thus, the efficacy of protective alleles is modulated by specific TCR clonotypes selected in natural infection, providing a functional explanation for divergent HIV-1 outcomes.