HLA-Cw*0102-restricted HIV-1 p24 epitope variants can modulate the binding of the inhibitory KIR2DL2 receptor and primary NK cell function.
HLA-Cw*0102-restricted HIV-1 p24 epitope variants can modulate the binding of the inhibitory KIR2DL2 receptor and primary NK cell function.
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DOI：
10.1371/journal.ppat.1002805
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Altfeld M
中科院分区：
文献类型：
--
作者：
Fadda L;Körner C;Kumar S;van Teijlingen NH;Piechocka-Trocha A;Carrington M;Altfeld M
越来越多的证据表明，自然杀伤（NK）细胞在控制HIV-1感染中发挥着重要作用。最近，研究表明NK细胞介导的免疫压力可以导致HIV-1逃逸突变的选择。这种NK细胞逃逸的潜在机制是选择HLA I类呈递的HIV-1表位，其允许抑制性杀伤细胞免疫球蛋白样受体（KIR），特别是KIR 2DL 2的参与。因此，我们研究了HLA-Cw*0102限制性表位内的序列变异对HLA-Cw*0102与KIR 2DL 2相互作用的影响，使用了大量重叠的HIV-1 p24 Gag肽。使用基于流式细胞术的测定，通过与Cw*0102（+）/TAP缺陷型T2细胞共孵育，筛选跨越HIV-1 p24 Gag共有序列的217个十聚体肽的HLA-Cw*0102稳定性。使用KIR 2DL 2-IgG融合构建体评估KIR 2DL 2结合。通过测量与肽脉冲的T2细胞共孵育后原代NK细胞的脱粒，流式细胞术分析KIR 2DL 2（+）NK细胞的功能。我们鉴定了11种稳定T2细胞表面HLA-Cw*0102的肽。然而，只有一种肽（p24 Gag 209 -218 AAEWDRLHPV）允许结合KIR 2DL 2。值得注意的是，功能分析显示，在p24 Gag 209 -218脉冲的T2细胞存在下，KIR 2DL 2（+）NK细胞的显著抑制，而KIR 2DL 2（-）NK细胞的脱粒不受影响。此外，我们证明了在天然存在的HIV-1序列中经常观察到的该表位的位置7的序列变异可以调节与KIR 2DL 2的结合。我们的研究结果表明，大多数HIV-1 p24 Gag肽稳定HLA-Cw*0102不允许结合KIR 2DL 2，但鉴定了一种HLA-Cw*0102呈递的肽（p24 Gag 209 -218），其被抑制性NK细胞受体KIR 2DL 2识别，导致表达KIR 2DL 2的NK细胞的功能抑制。KIR 2DL 2的参与可能保护病毒感染的细胞免受NK细胞介导的裂解，并且增加对KIR 2DL 2的亲合力的序列多态性的选择可能为HIV-1逃避NK细胞介导的免疫压力提供机制。区分“自我”和“非自我”是抵抗病毒感染的免疫反应的基本原则之一。在病毒感染后，由HLA I类分子呈递的肽库发生变化，潜在地提供导致宿主免疫系统识别和消除感染细胞的信号。病毒，特别是HIV-1，开发了多种策略来逃避T细胞和自然杀伤（NK）细胞介导的免疫压力，包括导致T细胞和NK细胞上表达的抑制性受体参与的序列变异。本研究中使用的系统方法鉴定出了一种HLA呈递的HIV-1肽，该肽可以与抑制性NK细胞受体KIR 2DL 2结合并抑制NK功能。我们的研究结果有助于阐明KIR分子（如KIR 2DL 2）与HLA/肽复合物之间的复杂相互作用，并为进一步研究HIV-1表位内序列变异对HLA/KIR相互作用的作用以及病毒逃避NK细胞介导的识别的能力提供基础。
Accumulating evidence suggests an important role for Natural Killer (NK) cells in the control of HIV-1 infection. Recently, it was shown that NK cell-mediated immune pressure can result in the selection of HIV-1 escape mutations. A potential mechanism for this NK cell escape is the selection of HLA class I-presented HIV-1 epitopes that allow for the engagement of inhibitory killer cell immunoglobulin-like receptors (KIRs), notably KIR2DL2. We therefore investigated the consequences of sequence variations within HLA-Cw*0102-restricted epitopes on the interaction of HLA-Cw*0102 with KIR2DL2 using a large panel of overlapping HIV-1 p24 Gag peptides. 217 decameric peptides spanning the HIV-1 p24 Gag consensus sequence were screened for HLA-Cw*0102 stabilization by co-incubation with Cw*0102(+)/TAP-deficient T2 cells using a flow cytometry-based assay. KIR2DL2 binding was assessed using a KIR2DL2-IgG fusion construct. Function of KIR2DL2(+) NK cells was flow cytometrically analyzed by measuring degranulation of primary NK cells after co-incubation with peptide-pulsed T2 cells. We identified 11 peptides stabilizing HLA-Cw*0102 on the surface of T2 cells. However, only one peptide (p24 Gag209–218 AAEWDRLHPV) allowed for binding of KIR2DL2. Notably, functional analysis showed a significant inhibition of KIR2DL2(+) NK cells in the presence of p24 Gag209–218-pulsed T2 cells, while degranulation of KIR2DL2(−) NK cells was not affected. Moreover, we demonstrated that sequence variations in position 7 of this epitope observed frequently in naturally occurring HIV-1 sequences can modulate binding to KIR2DL2. Our results show that the majority of HIV-1 p24 Gag peptides stabilizing HLA-Cw*0102 do not allow for binding of KIR2DL2, but identified one HLA-Cw*0102-presented peptide (p24 Gag209–218) that was recognized by the inhibitory NK cell receptor KIR2DL2 leading to functional inhibition of KIR2DL2-expressing NK cells. Engagement of KIR2DL2 might protect virus-infected cells from NK cell-mediated lysis and selections of sequence polymorphisms that increase avidity to KIR2DL2 might provide a mechanism for HIV-1 to escape NK cell-mediated immune pressure. Distinguishing between “self” and “non-self” is one of the fundamental principles of immune responses against viral infections. Upon viral infection the peptide repertoire presented by HLA class I molecules changes, potentially providing signals that result in recognition and elimination of the infected cell by the host immune system. Viruses, in particular HIV-1, developed multiple strategies to escape T cell and Natural Killer (NK) cell-mediated immune pressure, including sequence variations that lead to the engagement of inhibitory receptors expressed on T cells and NK cells. The systematic approach used in this study led to the identification of an HLA-presented HIV-1 peptide that allows engagement of the inhibitory NK cell receptor KIR2DL2 and inhibition of NK function. Our findings help to elucidate the complex interaction between KIR molecules, such as KIR2DL2, and HLA/peptide complexes and provide a foundation for further studies investigating the role of sequence variations within HIV-1 epitopes on HLA/KIR interactions, and the ability of viruses to evade NK cell-mediated recognition.
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DOI：
10.1073/pnas.071548198
发表时间：
2001-04-24
影响因子：
11.1
作者：
Flores-Villanueva, PO;Yunis, EJ;Goldfeld, AE
通讯作者：
Goldfeld, AE
影响因子：
56.9
作者：
MALNATI, MS;PERUZZI, M;LONG, EO
通讯作者：
LONG, EO
影响因子：
15.3
作者：
Barber, LD;Percival, L;Parham, P
通讯作者：
Parham, P
DOI：
10.1084/jem.20072457
发表时间：
2008-05-12
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Goepfert PA;Lumm W;Farmer P;Matthews P;Prendergast A;Carlson JM;Derdeyn CA;Tang J;Kaslow RA;Bansal A;Yusim K;Heckerman D;Mulenga J;Allen S;Goulder PJ;Hunter E
通讯作者：
Hunter E
影响因子：
5.4
作者：
Brackenridge, Simon;Evans, Edward J.;Gillespie, Geraldine M.
通讯作者：
Gillespie, Geraldine M.