Immunogenetic studies have shown that specific HLA-B residues (67, 70, 97, and 156) mediate the impact of HLA class I on HIV infection, but the molecular basis is not well understood. Here we evaluate the function of these residues within the protective HLA-B^∗5701 allele. While mutation of Met67, Ser70, and Leu156 disrupt CD8⁺ T cell recognition, substitution of Val97 had no significant impact. Thermal denaturation of HLA-B^∗5701-peptide complexes revealed that Met67 and Leu156 maintain HLA-peptide stability, while Ser70 and Leu156 facilitate T cell receptor (TCR) interactions. Analyses of existing structures and structural models suggested that Val97 mediates HLA-peptide binding to inhibitory KIR3DL1 molecules, which was confirmed by experimental assays. These data thereby demonstrate that the genetic basis by which host immunity impacts HIV outcomes occurs by modulating HLA-B-peptide stability and conformation for interaction with TCR and killer immunoglobulin receptor (KIR) molecules. Moreover, they indicate a key role for epitope specificity and HLA-KIR interactions to HIV control.

免疫遗传学研究表明，特定的 HLA-B 残基（67、70、97 和 156）介导 I 类 HLA 对 HIV 感染的影响，但其分子基础尚不清楚。在这里，我们评估了保护性HLA-B ^* 5701等位基因中这些残基的功能。虽然 Met67、Ser70 和 Leu156 的突变破坏了 CD8 ⁺ T 细胞的识别，但 Val97 的替换没有显着影响。 HLA-B ^* 5701-肽复合物的热变性表明，Met67 和 Leu156 保持 HLA-肽稳定性，而 Ser70 和 Leu156 促进 T 细胞受体 (TCR) 相互作用。对现有结构和结构模型的分析表明，Val97 介导 HLA 肽与抑制性 KIR3DL1 分子的结合，这已通过实验测定得到证实。因此，这些数据表明，宿主免疫影响 HIV 结果的遗传基础是通过调节 HLA-B 肽稳定性和与 TCR 和杀伤性免疫球蛋白受体 (KIR) 分子相互作用的构象而发生的。此外，它们表明表位特异性和 HLA-KIR 相互作用对 HIV 控制具有关键作用。