Department of Microbiology, Immunology & Tropical Medicine, The George Washington University, Washington DC, United States of America.
Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada.
PLoS Pathog. 2018 Sep 4;14(9):e1007257. doi: 10.1371/journal.ppat.1007257. eCollection 2018 Sep.
HIV-1 can downregulate HLA-C on infected cells, using the viral protein Vpu, and the magnitude of this downregulation varies widely between primary HIV-1 variants. The selection pressures that result in viral downregulation of HLA-C in some individuals, but preservation of surface HLA-C in others are not clear. To better understand viral immune evasion targeting HLA-C, we have characterized HLA-C downregulation by a range of primary HIV-1 viruses. 128 replication competent viral isolates from 19 individuals with effective anti-retroviral therapy, show that a substantial minority of individuals harbor latent reservoir virus which strongly downregulates HLA-C. Untreated infections display no change in HLA-C downregulation during the first 6 months of infection, but variation between viral quasispecies can be detected in chronic infection. Vpu molecules cloned from plasma of 195 treatment naïve individuals in chronic infection demonstrate that downregulation of HLA-C adapts to host HLA genotype. HLA-C alleles differ in the pressure they exert for downregulation, and individuals with higher levels of HLA-C expression favor greater viral downregulation of HLA-C. Studies of primary and mutant molecules identify 5 residues in the transmembrane region of Vpu, and 4 residues in the transmembrane domain of HLA-C, which determine interactions between Vpu and HLA. The observed adaptation of Vpu-mediated downregulation to host genotype indicates that HLA-C alleles differ in likelihood of mediating a CTL response that is subverted by viral downregulation, and that preservation of HLA-C expression is favored in the absence of these responses. Finding that latent reservoir viruses can downregulate HLA-C could have implications for HIV-1 cure therapy approaches in some individuals.
HIV-1 可以使用病毒蛋白 Vpu 下调感染细胞上的 HLA-C，并且这种下调的程度在不同的 HIV-1 原始变体之间差异很大。导致在某些个体中病毒下调 HLA-C，但在其他个体中保留表面 HLA-C 的选择压力尚不清楚。为了更好地了解针对 HLA-C 的病毒免疫逃避，我们已经对一系列 HIV-1 原始病毒进行了 HLA-C 下调的特征描述。19 名接受有效抗逆转录病毒治疗的个体的 128 个具有复制能力的病毒分离株表明，相当一部分个体携带强烈下调 HLA-C 的潜伏储库病毒。未经治疗的感染在感染的头 6 个月期间不会改变 HLA-C 下调，但在慢性感染中可以检测到病毒准种之间的差异。从慢性感染的 195 名未经治疗的个体的血浆中克隆的 Vpu 分子表明，HLA-C 的下调适应了宿主 HLA 基因型。HLA-C 等位基因在其施加的下调压力方面存在差异，具有更高 HLA-C 表达水平的个体有利于 HLA-C 的更大下调。对原始和突变分子的研究确定了 Vpu 跨膜区中的 5 个残基和 HLA-C 跨膜结构域中的 4 个残基，这些残基决定了 Vpu 和 HLA 之间的相互作用。观察到 Vpu 介导的下调对宿主基因型的适应性表明，HLA-C 等位基因在介导 CTL 反应的可能性方面存在差异，这些反应被病毒下调所颠覆，并且在缺乏这些反应的情况下，HLA-C 表达的保留受到青睐。发现潜伏储库病毒可以下调 HLA-C，这可能对某些个体的 HIV-1 治愈治疗方法产生影响。
