It was widely accepted that HIV-1 downregulates HLA-A/B to avoid CTL recognition while leaving HLA-C unaltered in order to prevent NK cell activation by engaging inhibitory NK cell receptors, but it was recently observed that most primary isolates of HIV-1 can mediate HLA-C downmodulation. Now we report that HIV-1-mediated downmodulation of HLA-C was associated with reduced binding to its respective inhibitory receptors. Despite this, HLA-C-licensed NK cells displayed reduced antiviral activity compared to their unlicensed counterparts, potentially due to residual binding to the respective inhibitory receptors. Nevertheless, NK cells were able to sense alterations of HLA-C expression demonstrated by increased antiviral activity when exposed to viral strains with differential abilities to downmodulate HLA-C. These results suggest that the capability of HLA-C-licensed NK cells to control HIV-1 replication is determined by the strength of KIR/HLA-C interactions and is thus dependent on both host genetics and the extent of virus-mediated HLA-C downregulation.

人们普遍认为，HIV-1 下调 HLA-A/B 以避免 CTL 识别，同时保持 HLA-C 不变，从而通过接合抑制性 NK 细胞受体来防止 NK 细胞激活，但最近观察到，大多数 HIV 的初级分离株1 可以介导 HLA-C 下调。现在我们报道 HIV-1 介导的 HLA-C 下调与其各自抑制性受体的结合减少有关。尽管如此，与未经 HLA-C 许可的 NK 细胞相比，获得 HLA-C 许可的 NK 细胞表现出较低的抗病毒活性，这可能是由于与各自抑制性受体的残留结合所致。然而，当暴露于下调 HLA-C 能力不同的病毒株时，NK 细胞能够感知 HLA-C 表达的变化，表现为抗病毒活性增加。这些结果表明，HLA-C 许可的 NK 细胞控制 HIV-1 复制的能力是由 KIR/HLA-C 相互作用的强度决定的，因此取决于宿主遗传学和病毒介导的 HLA-C 的程度。下调。