Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS
Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS
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DOI：
10.1038/ng934
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发表时间：
2002-08-01
期刊：
影响因子：
30.8
通讯作者：
Carrington, M
中科院分区：
文献类型：
--
作者：
Martin, MP;Gao, XJ;Carrington, M
自然杀伤（NK）细胞通过产生细胞因子和引起细胞毒性，在先天免疫应答的早期阶段为病毒感染提供防御(1)。NK细胞上的杀伤性免疫球蛋白样受体（KIRs）通过识别靶细胞上的人白细胞抗原（HLA） I类分子来调节NK细胞反应的抑制和激活(2)。KIR和HLA位点都是高度多态性的，一些HLA I类产物结合并触发KIR基因指定的细胞表面受体。在这里，我们报道了激活的KIR等位基因KIR3DS1，与编码80位异亮氨酸分子的HLA-B等位基因（HLA-B Bw4-80Ile）结合，与感染人类免疫缺陷病毒1型（HIV-1）的个体延迟进展为艾滋病有关。在缺乏KIR3DS1的情况下，HLA-B Bw4-80Ile等位基因与所测量的任何艾滋病结果都没有关联。相比之下，在缺乏HLA-B Bw4-80Ile等位基因的情况下，KIR3DS1与更快发展为艾滋病显著相关。这些观察结果强烈地暗示了一个涉及两个位点之间上位性相互作用的模型。这些位点最强的协同作用是在CD4(+) T细胞的耗竭过程中，这表明NK细胞涉及KIR3DS1及其HLA I类配体的保护性反应在HIV-1感染后不久就开始了。
Natural killer (NK) cells provide defense in the early stages of the innate immune response against viral infections by producing cytokines and causing cytotoxicity(1). The killer immunoglobulin-like receptors (KIRs) on NK cells regulate the inhibition and activation of NK-cell responses through recognition of human leukocyte antigen (HLA) class I molecules on target cells(2). KIR and HLA loci are both highly polymorphic, and some HLA class I products bind and trigger cell-surface receptors specified by KIR genes. Here we report that the activating KIR allele KIR3DS1, in combination with HLA-B alleles that encode molecules with isoleucine at position 80 (HLA-B Bw4-80Ile), is associated with delayed progression to AIDS in individuals infected with human immunodeficiency virus type 1 (HIV-1). In the absence of KIR3DS1, the HLA-B Bw4-80Ile allele was not associated with any of the AIDS outcomes measured. By contrast, in the absence of HLA-B Bw4-80Ile alleles, KIR3DS1 was significantly associated with more rapid progression to AIDS. These observations are strongly suggestive of a model involving an epistatic interaction between the two loci. The strongest synergistic effect of these loci was on progression to depletion of CD4(+) T cells, which suggests that a protective response of NK cells involving KIR3DS1 and its HLA class I ligands begins soon after HIV-1 infection.