HLA-C-mediated antigen presentation induces the killing of human immunodeficiency virus (HIV)-infected CD4⁺ T cells by cytotoxic T lymphocytes (CTLs). To evade killing, many HIV-1 group M strains decrease HLA-C surface levels using their accessory protein Vpu. However, some HIV-1 group M isolates lack this activity, possibly to prevent the activation of natural killer (NK) cells. Analyzing diverse primate lentiviruses, we found that Vpu-mediated HLA-C downregulation is not limited to pandemic group M but is also found in HIV-1 groups O and P as well as several simian immunodeficiency viruses (SIVs). We show that Vpu targets HLA-C primarily at the protein level, independently of its ability to suppress NF-κB-driven gene expression, and that in some viral lineages, HLA-C downregulation may come at the cost of efficient counteraction of the restriction factor tetherin. Remarkably, HIV-2, which does not carry a vpu gene, uses its accessory protein Vif to decrease HLA-C surface expression. This Vif activity requires intact binding sites for the Cullin5/Elongin ubiquitin ligase complex but is separable from its ability to counteract APOBEC3G. Similar to HIV-1 Vpu, the degree of HIV-2 Vif-mediated HLA-C downregulation varies considerably among different virus isolates. In agreement with opposing selection pressures in vivo, we show that the reduction of HLA-C surface levels by HIV-2 Vif is accompanied by increased NK cell-mediated killing. In summary, our results highlight the complex role of HLA-C in lentiviral infections and demonstrate that HIV-1 and HIV-2 have evolved at least two independent mechanisms to decrease HLA-C levels on infected cells.

中文翻译：

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HIV-1 和 HIV-2 中 HLA-C 下调的趋同进化。


HLA-C 介导的抗原呈递诱导细胞毒性 T 淋巴细胞 (CTL) 杀死人类免疫缺陷病毒 (HIV) 感染的 CD4 ⁺ T 细胞。为了逃避杀戮，许多 HIV-1 M 组毒株利用其辅助蛋白 Vpu 降低 HLA-C 表面水平。然而，一些 HIV-1 M 组分离株缺乏这种活性，可能是为了阻止自然杀伤 (NK) 细胞的激活。通过分析多种灵长类慢病毒，我们发现 Vpu 介导的 HLA-C 下调不仅限于大流行的 M 组，还存在于 HIV-1 O 组和 P 组以及几种猿猴免疫缺陷病毒 (SIV) 中。我们表明，Vpu 主要在蛋白质水平上靶向 HLA-C，与其抑制 NF-κB 驱动的基因表达的能力无关，并且在某些病毒谱系中，HLA-C 下调可能会以有效抵消限制性作用为代价。因子系链蛋白。值得注意的是，HIV-2 不携带vpu基因，但它利用其辅助蛋白 Vif 来降低 HLA-C 表面表达。这种 Vif 活性需要 Cullin5/Elongin 泛素连接酶复合物的完整结合位点，但与其抵消 APOBEC3G 的能力是分开的。与 HIV-1 Vpu 类似，HIV-2 Vif 介导的 HLA-C 下调程度在不同病毒分离株之间差异很大。与体内相反的选择压力一致，我们表明 HIV-2 Vif 降低 HLA-C 表面水平伴随着 NK 细胞介导的杀伤增加。总之，我们的结果强调了 HLA-C 在慢病毒感染中的复杂作用，并证明 HIV-1 和 HIV-2 已经进化出至少两种独立的机制来降低受感染细胞上的 HLA-C 水平。