Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, Massachusetts, USA.
Nat Immunol. 2012 Jun 10;13(7):691-700. doi: 10.1038/ni.2342.
The human leukocyte antigens HLA-B27 and HLA-B57 are associated with protection against progression of disease that results from infection with human immunodeficiency virus type 1 (HIV-1), yet most people with alleles encoding HLA-B27 and HLA-B57 are unable to control HIV-1. Here we found that HLA-B27-restricted CD8(+) T cells in people able to control infection with HIV-1 (controllers) and those who progress to disease after infection with HIV-1 (progressors) differed in their ability to inhibit viral replication through targeting of the immunodominant epitope of group-associated antigen (Gag) of HIV-1. This was associated with distinct T cell antigen receptor (TCR) clonotypes, characterized by superior control of HIV-1 replication in vitro, greater cross-reactivity to epitope variants and enhanced loading and delivery of perforin. We also observed clonotype-specific differences in antiviral efficacy for an immunodominant HLA-B57-restricted response in controllers and progressors. Thus, the efficacy of such so-called 'protective alleles' is modulated by specific TCR clonotypes selected during natural infection, which provides a functional explanation for divergent HIV-1 outcomes.
人类白细胞抗原 HLA-B27 和 HLA-B57 与感染人类免疫缺陷病毒 1 型 (HIV-1) 后疾病进展的保护有关，但大多数携带 HLA-B27 和 HLA-B57 等位基因的人无法控制 HIV-1。在这里，我们发现能够控制 HIV-1 感染的人（控制者）和感染 HIV-1 后进展为疾病的人（进展者）中，HLA-B27 限制的 CD8(+) T 细胞在抑制病毒复制方面存在差异通过针对 HIV-1 群相关抗原 (Gag) 的免疫优势表位进行靶向。这与独特的 T 细胞抗原受体 (TCR) 克隆型有关，其特征是在体外更好地控制 HIV-1 复制、对表位变体具有更高的交叉反应性以及增强穿孔素的加载和递送。我们还观察到在控制者和进展者中，针对免疫优势 HLA-B57 限制反应的克隆型特异性抗病毒功效的差异。因此，这种所谓的“保护性等位基因”的功效受到自然感染过程中选择的特定 TCR 克隆型的调节，这为 HIV-1 结果的差异提供了功能解释。
