Blockade of the PD-1 axis alone is not sufficient to activate HIV-1 virion production from CD4+ T cells of individuals on suppressive ART
Blockade of the PD-1 axis alone is not sufficient to activate HIV-1 virion production from CD4+ T cells of individuals on suppressive ART
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DOI：
10.1371/journal.pone.0211112
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发表时间：
2019-01-25
期刊：
影响因子：
3.7
通讯作者：
Mellors, John W.
中科院分区：
文献类型：
--
作者：
Bui, John K.;Cyktor, Joshua C.;Mellors, John W.
使用单克隆抗体 (mAb) 阻断程序性细胞死亡蛋白/配体 1 (PD-1/PD-L1) 通路目前常用于癌症免疫治疗，并且对包括 HIV-1 在内的慢性病毒感染具有治疗潜力。 PD-1/PD-L1阻断可以增强HIV-1特异性免疫反应并逆转HIV-1潜伏期，但后者的作用尚未明确显示。我们测试了人抗 PD-L1 mAb BMS-936559 和人抗 PD-1 mAb nivolumab 增加来自接受抑制性抗逆转录病毒治疗 (ART) 捐献者的不同外周血单核细胞群离体产生 HIV-1 病毒颗粒的能力。从 HIV-1 感染供者的全血中纯化新鲜外周血单核细胞 (PBMC)、CD8 耗尽的 PBMC、总 CD4(+) T 细胞和静息 CD4(+) T 细胞，并在不同浓度的 BMS-936559（20、5 或 1.25 μg/mL）或纳武单抗（5 或 1.25 μg/mL）中培养，有或没有抗CD3/CD28刺激抗体。通过 qRT-PCR 检测培养物上清液中的病毒粒子 HIV-1 RNA。离体暴露于 BMS-936559 或纳武单抗，无论有或没有抗 CD3/CD28 刺激，都不会持续增加血液单核细胞群中 HIV-1 病毒颗粒的产生。在一部分供体和某些细胞类型中观察到病毒产量适度（2倍）增加，但在纵向样本中无法重现。 PD-1 和 PD-L1 的细胞表面表达与病毒产生的变化无关。单独体外阻断 PD-1 轴对 HIV-1 潜伏期的影响有限。
Blockade of the programmed cell death protein/ligand 1 (PD-1/PD-L1) pathway with monoclonal antibodies (mAb) is now commonly used for cancer immunotherapy and has therapeutic potential in chronic viral infections including HIV-1. PD-1/PD-L1 blockade could augment HIV-1-specific immune responses and reverse HIV-1 latency, but the latter effect has not been clearly shown. We tested the ability of the human anti-PD-L1 mAb BMS-936559 and the human anti-PD-1 mAb nivolumab to increase HIV-1 virion production ex vivo from different peripheral blood mononuclear cell populations obtained from donors on suppressive antiretroviral therapy (ART). Fresh peripheral blood mononuclear cells (PBMC), CD8-depleted PBMC, total CD4(+) T cells, and resting CD4(+) T cells were purified from whole blood of HIV-1-infected donors and cultured in varying concentrations of BMS-936559 (20, 5, or 1.25 mu g/mL) or nivolumab (5 or 1.25 mu g/mL), with or without anti-CD3/CD28 stimulatory antibodies. Culture supernatants were assayed for virion HIV-1 RNA by qRT-PCR. Ex vivo exposure to BMS-936559 or nivolumab, with or without anti-CD3/CD28 stimulation, did not consistently increase HIV-1 virion production from blood mononuclear cell populations. Modest (2-fold) increases in virus production were observed in a subset of donors and in some cell types but were not reproducible in longitudinal samples. Cell surface expression of PD-1 and PD-L1 were not associated with changes in virus production. Ex vivo blockade of the PD-1 axis alone has limited effects on HIV-1 latency.