Host KIR/HLA-C Genotypes Determine HIV-Mediated Changes of the NK Cell Repertoire and Are Associated With Vpu Sequence Variations Impacting Downmodulation of HLA-C.
Host KIR/HLA-C Genotypes Determine HIV-Mediated Changes of the NK Cell Repertoire and Are Associated With Vpu Sequence Variations Impacting Downmodulation of HLA-C.
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宿主KIR/HLA-C基因型确定了NK细胞库的HIV介导的变化，并与影响HLA-C下调的VPU序列变化有关。
DOI：
10.3389/fimmu.2022.922252
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
自然杀伤（NK）细胞在病毒免疫中起着关键作用，它利用大量的激活受体和抑制受体来识别和清除病毒感染细胞。杀伤细胞免疫球蛋白样受体（KIRs）是一个高度多态的受体家族，可调节NK细胞活性并决定识别靶细胞的能力。人类白细胞抗原（HLA）I类分子是KIRs的主要配体。在此，HLA - C是大多数KIRs的主要配体。越来越多的证据表明，HLA - C与其抑制性KIR2DL受体（KIR2DL1/L2/L3）之间的相互作用可促使HIV - 1介导的免疫逃逸，从而可能有助于对HIV - 1感染的内在控制。在这种情况下，特别令人感兴趣的是最近的观察结果，即HIV - 1能够通过Vpu介导的HLA - C下调来适应宿主HLA - C基因型。然而，我们对KIR/HLA免疫遗传学、NK细胞介导的免疫压力和HIV - 1免疫逃逸之间复杂的相互作用的理解仍然有限。因此，我们研究了特定的KIR/HLA - C组合对122名未经治疗的病毒血症HIV - 1阳性个体的NK细胞受体库以及HIV - 1 Vpu蛋白序列变异的影响。与60名HIV - 1阴性对照相比，HIV - 1感染与NK细胞受体库内的显著变化有关，包括表达NKG2A、CD8和KIR2DS4的NK细胞百分比降低。相反，与HIV - 1阴性对照相比，HIV - 1阳性个体的NKG2C⁺和KIR3DL2⁺NK细胞亚群增大。按照KIR/HLA - C基因型分层显示，KIR2DL1⁺NK细胞呈基因型依赖性扩增，这最终与KIR2DL1和HLA - C同种异型之间的结合亲和力增加有关。最后，我们的数据暗示在KIR2DL/HLA - C结合亲和力高的个体中，存在与HLA - C下调相关的Vpu序列变异的优先选择。总之，我们的研究提供的证据表明，NK细胞KIR库中与HIV - 1相关的变化在一定程度上由宿主KIR2DL/HLA - C基因型预先决定。此外，对Vpu序列多态性的分析表明，不同的KIR2DL/HLA - C结合亲和力可能是宿主遗传学影响HIV - 1免疫逃逸的另一种机制。
NK cells play a pivotal role in viral immunity, utilizing a large array of activating and inhibitory receptors to identify and eliminate virus-infected cells. Killer-cell immunoglobulin-like receptors (KIRs) represent a highly polymorphic receptor family, regulating NK cell activity and determining the ability to recognize target cells. Human leukocyte antigen (HLA) class I molecules serve as the primary ligand for KIRs. Herein, HLA-C stands out as being the dominant ligand for the majority of KIRs. Accumulating evidence indicated that interactions between HLA-C and its inhibitory KIR2DL receptors (KIR2DL1/L2/L3) can drive HIV-1-mediated immune evasion and thus may contribute to the intrinsic control of HIV-1 infection. Of particular interest in this context is the recent observation that HIV-1 is able to adapt to host HLA-C genotypes through Vpu-mediated downmodulation of HLA-C. However, our understanding of the complex interplay between KIR/HLA immunogenetics, NK cell-mediated immune pressure and HIV-1 immune escape is still limited. Therefore, we investigated the impact of specific KIR/HLA-C combinations on the NK cell receptor repertoire and HIV-1 Vpu protein sequence variations of 122 viremic, untreated HIV-1+ individuals. Compared to 60 HIV-1- controls, HIV-1 infection was associated with significant changes within the NK cell receptor repertoire, including reduced percentages of NK cells expressing NKG2A, CD8, and KIR2DS4. In contrast, the NKG2C+ and KIR3DL2+ NK cell sub-populations from HIV-1+ individuals was enlarged compared to HIV-1- controls. Stratification along KIR/HLA-C genotypes revealed a genotype-dependent expansion of KIR2DL1+ NK cells that was ultimately associated with increased binding affinities between KIR2DL1 and HLA-C allotypes. Lastly, our data hinted to a preferential selection of Vpu sequence variants that were associated with HLA-C downmodulation in individuals with high KIR2DL/HLA-C binding affinities. Altogether, our study provides evidence that HIV-1-associated changes in the KIR repertoire of NK cells are to some extent predetermined by host KIR2DL/HLA-C genotypes. Furthermore, analysis of Vpu sequence polymorphisms indicates that differential KIR2DL/HLA-C binding affinities may serve as an additional mechanism how host genetics impact immune evasion by HIV-1.
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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
DOI：
10.4049/jimmunol.1001494
发表时间：
2010-10-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Older Aguilar AM;Guethlein LA;Adams EJ;Abi-Rached L;Moesta AK;Parham P
通讯作者：
Parham P
影响因子：
20.3
作者：
Gumá, M;Angulo, A;López-Botet, M
通讯作者：
López-Botet, M
影响因子：
16.8
作者：
Boudreau JE;Hsu KC
通讯作者：
Hsu KC
DOI：
10.1002/iid3.178
发表时间：
2017-12
期刊：
Immunity, inflammation and disease
影响因子：
--
作者：
Blokhuis JH;Hilton HG;Guethlein LA;Norman PJ;Nemat-Gorgani N;Nakimuli A;Chazara O;Moffett A;Parham P
通讯作者：
Parham P