HLA-C downregulation by HIV-1 adapts to host HLA genotype.
HLA-C downregulation by HIV-1 adapts to host HLA genotype.
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DOI：
10.1371/journal.ppat.1007257
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发表时间：
2018-09
期刊：
影响因子：
6.7
通讯作者：
Apps R
中科院分区：
文献类型：
--
作者：
Bachtel ND;Umviligihozo G;Pickering S;Mota TM;Liang H;Del Prete GQ;Chatterjee P;Lee GQ;Thomas R;Brockman MA;Neil S;Carrington M;Bwana B;Bangsberg DR;Martin JN;Kallas EG;Donini CS;Cerqueira NB;O'Doherty UT;Hahn BH;Jones RB;Brumme ZL;Nixon DF;Apps R
HIV-1可以使用病毒蛋白Vpu下调感染细胞上的HLA-C，并且这种下调的幅度在主要HIV-1变体之间变化很大。选择压力导致一些个体中HLA-C的病毒下调，但另一些个体中表面HLA-C的保留尚不清楚。为了更好地理解靶向HLA-C的病毒免疫逃避，我们已经表征了一系列主要HIV-1病毒对HLA-C的下调。来自19名接受有效抗逆转录病毒治疗的个体的128个复制能力病毒分离株显示，相当少的个体携带强烈下调HLA-C的潜伏性储库病毒。未经治疗的感染在感染的前6个月内HLA-C下调没有变化，但在慢性感染中可以检测到病毒准种之间的变化。从195个慢性感染的未经治疗的个体的血浆中克隆的Vpu分子表明，HLA-C的下调适应宿主HLA基因型。HLA-C等位基因在它们对下调施加的压力方面不同，并且具有较高水平的HLA-C表达的个体有利于HLA-C的更大的病毒下调。对初级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，它们决定了Vpu和HLA之间的相互作用。所观察到的Vpu介导的下调对宿主基因型的适应表明HLA-C等位基因在介导被病毒下调破坏的CTL应答的可能性方面不同，并且在不存在这些应答的情况下有利于HLA-C表达的保留。发现潜伏的储库病毒可以下调HLA-C可能对某些个体的HIV-1治愈治疗方法有影响。HLA-C是主要组织相容性复合体I类（MHC-I）分子家族的成员，其是先天性和适应性免疫的许多应答的组成部分。HIV-1可以使用病毒蛋白Vpu下调受感染细胞上HLA-C的表达水平，但HLA-C下调的幅度在原代HIV病毒之间差异很大。这提供了一个机会，以确定在受感染的人类个体的HLA-C表达的相反的压力。我们发现HLA-C的病毒下调与宿主和病毒基因型相关，定义了HLA-C和Vpu的等位基因差异，这将有助于识别导致HLA-C病毒下调或保留的特异性免疫反应。这些反应可以代表免疫治疗的候选者，因为它们在体内表现出的效果。我们还发现，来自某些个体的潜伏储库的HIV-1病毒可以下调HLA-C，这表明在某些个体中，HIV-1的治愈将需要去除能够下调HLA-C的病毒。HLA-C的独特作用，施加选择压力，导致其表达的可变调节，如果可以在同一个体中建立对HLA-C表达的两种相反压力，则可能使免疫疗法实现增强的功效。
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. HLA-C is a member of the major histocompatibility complex class-I (MHC-I) family of molecules which are integral to many responses of innate and adaptive immunity. HIV-1 can downregulate the expression level of HLA-C on infected cells, using the viral protein Vpu, but the magnitude of HLA-C downregulation varies widely between primary HIV viruses. This provides an opportunity to identify opposing pressures on HLA-C expression in infected human individuals. We find that viral downregulation of HLA-C associates with both host and virus genotype, defining allelic differences in HLA-C and Vpu that will help to identify the specific immune responses which result in viral downregulation or preservation of HLA-C. These responses could represent candidates for immune therapy, given their demonstrated effects in vivo. We also find that HIV-1 viruses from the latent reservoir of some individuals can downregulate HLA-C, indicating that in certain individuals HIV-1 cure will require the removal of virus that is able to downregulate HLA-C. The unique role of HLA-C, exerting selection pressures that result in variable modulation of its expression, may make it possible for immunotherapies to achieve enhanced efficacy if both of the opposing pressures on HLA-C expression could be established in the same individual.
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影响因子：
6.7
作者：
Fadda L;Körner C;Kumar S;van Teijlingen NH;Piechocka-Trocha A;Carrington M;Altfeld M
通讯作者：
Altfeld M
影响因子：
9.2
作者：
Braud, VM;Allan, DSJ;McMichael, AJ
通讯作者：
McMichael, AJ
影响因子：
56.9
作者：
DEACON, NJ;TSYKIN, A;MILLS, J
通讯作者：
MILLS, J
DOI：
10.4049/jimmunol.1103472
发表时间：
2012-05-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
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作者：
Blais ME;Zhang Y;Rostron T;Griffin H;Taylor S;Xu K;Yan H;Wu H;James I;John M;Dong T;Rowland-Jones SL
通讯作者：
Rowland-Jones SL
DOI：
10.4049/jimmunol.1403234
发表时间：
2015-04-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Apps R;Meng Z;Del Prete GQ;Lifson JD;Zhou M;Carrington M
通讯作者：
Carrington M