Human leukocyte antigen (HLA) alleles have been linked to HIV disease progression and attributed to differences in cytotoxic T lymphocyte (CTL) epitope representation. These findings are largely based on treatment-naive individuals of European and African ancestry. We assessed HLA associations with HIV-1 outcomes in 1,318 individuals from Thailand and found HLA-B∗46:01 (B∗46) associated with accelerated disease in three independent cohorts. B∗46 had no detectable effect on HIV-specific T cell responses, but this allele is unusual in containing an HLA-C epitope that binds inhibitory receptors on natural killer (NK) cells. Unbiased transcriptomic screens showed increased NK cell activation in people with HIV, without B∗46, and simultaneous single-cell profiling of surface proteins and transcriptomes revealed a NK cell subset primed for increased responses in the absence of B∗46. These findings support a role for NK cells in HIV pathogenesis, revealed by the unique properties of the B∗46 allele common only in Asia.

人类白细胞抗原 ( HLA ) 等位基因与 HIV 疾病进展有关，并归因于细胞毒性 T 淋巴细胞 (CTL) 表位表示的差异。这些发现主要基于欧洲和非洲血统的未接受治疗的个体。我们评估了 HLA与来自泰国的 1,318 名个体的 HIV-1 结果相关，并在三个独立队列中发现 HLA-B*46:01 (B*46) 与疾病加速相关。B∗46 对 HIV 特异性 T 细胞反应没有可检测到的影响，但这种等位基因在含有与自然杀伤 (NK) 细胞上的抑制性受体结合的 HLA-C 表位时是不寻常的。无偏转录组筛选显示，在没有 B*46 的情况下，HIV 感染者的 NK 细胞活化增加，同时对表面蛋白和转录组进行单细胞分析显示，在没有 B*46 的情况下，NK 细胞亚群已准备好增加反应。这些发现支持 NK 细胞在 HIV 发病机制中的作用，这一点由仅在亚洲常见的 B*46 等位基因的独特特性所揭示。