Antibody-Dependent Cellular Cytotoxicity Activity of Effector Cells from HIV-Infected Elite and Viral Controllers
Antibody-Dependent Cellular Cytotoxicity Activity of Effector Cells from HIV-Infected Elite and Viral Controllers
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DOI：
10.1089/aid.2016.0157
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发表时间：
2016-10-01
影响因子：
1.5
通讯作者：
Bernard, Nicole F.
中科院分区：
文献类型：
--
作者：
Isitman, Gamze;Lisovsky, Irene;Bernard, Nicole F.
携带编码某些抑制性自然杀伤（NK）细胞受体/HLA配体KIR 3DL 1/HLA-B组合的等位基因与保护免受HIV感染和延缓AIDS的时间相关，这暗示NK细胞在HIV控制中。NK细胞还介导抗体依赖性细胞毒性（ADCC）。在中等保护性RV 144泰国HIV疫苗试验的二次分析中，ADCC已被确定为与保护相关。在ADCC中，HIV包膜（Env）特异性抗体（Ab）桥接HIV感染或gp 120包被的靶细胞和表达Ab Fc结构域的CD 16受体的NK细胞。CD 16接合激活NK细胞以分泌细胞因子/趋化因子、去活化、将颗粒酶B（GrB）递送至靶细胞和细胞溶解。HIV+受试者的一个子集，称为缓慢进展者（SP），在未经治疗的情况下维持低水平的病毒血症。与进展者相比，HIV+ SP具有更高的滴度和/或更大的ADCC活性Ab宽度。缺乏对HIV+受试者中CD 16参与后NK效应细胞功能能力的研究。我们使用ADCC-GranToxiLux（ADCC-GTL）试验评估了在存在抗Env Ab的情况下，由来自37个HIV+ SP和15个进展者的效应细胞产生的GrB+（%GrB+）细胞到gp 120包被的CEM.NKr.CCR5靶细胞的频率。受试者组根据他们是否携带能够赋予NK细胞功能潜力的教育性KIR 3DL 1/HLA-B组合进行分层。未观察到由来自教育型与非教育型KIR 3DL 1/HLA-B对携带者的效应细胞产生的%GrB+靶细胞的差异。NK细胞教育对该读数没有影响可能是由于来自SP的受教育NK细胞对Ab依赖性刺激的应答能力丧失和/或KIR 3DL 1（+）的频率低于共表达CD 16的KIR 3DL 1（-）NK细胞。KIR/HLA基因型对ADCC效力的个体间差异影响最小，这与靶向ADCC以控制HIV的治疗干预有关。
Carriage of alleles encoding certain inhibitory natural killer (NK) cell receptor/HLA ligand KIR3DL1/HLA-B combinations is associated with protection from HIV infection and slow time to AIDS, implicating NK cells in HIV control. NK cells also mediate antibody-dependent cellular cytotoxicity (ADCC). ADCC has been identified as a correlate of protection in secondary analyses of the modestly protective RV144 Thai HIV vaccine trial. In ADCC, HIV envelope (Env)-specific antibodies (Abs) bridge HIV-infected or gp120-coated target cells and NK cells expressing CD16 receptors for Ab Fc domains. CD16 engagement activates NK cells to secrete cytokines/chemokines, degranulate, deliver granzyme B (GrB) to target cells, and cytolysis. A subset of HIV+ subjects, known as slow progressors (SPs), maintains low-level viremia without treatment. HIV+ SPs versus progressors have higher titers and/or a greater breadth of ADCC-competent Abs. Investigations of the functional capacity of NK effector cells following CD16 engagement in HIV+ subjects are lacking. We used the ADCC-GranToxiLux (ADCC-GTL) assay to assess the frequency of GrB+ (%GrB+) cells generated by effector cells from 37 HIV+ SPs and 15 progressors to gp120-coated CEM.NKr.CCR5 target cells in the presence of anti-Env Abs. Subject groups were stratified according to whether or not they carried educating KIR3DL1/HLA-B combinations able to confer NK cells with functional potential. No differences were observed in %GrB+ target cells generated by effector cells from carriers of educating versus noneducating KIR3DL1/HLA-B pairs. The absence of an effect of NK cell education on this readout may be due to loss of the ability of educated NK cells from SPs to respond to Ab-dependent stimulation and/or the lower frequency of KIR3DL1(+) than KIR3DL1(-) NK cells that coexpress CD16. That KIR/HLA genotypes have minimal impact on interindividual differences in ADCC potency has relevance for therapeutic interventions that target ADCC for HIV control.