The inhibitor of apoptosis proteins antagonist Debio 1143 promotes the PD-1 blockade-mediated HIV load reduction in blood and tissues of humanized mice

The immune checkpoint programmed cell death protein 1 (PD-1) plays a major role in T cell exhaustion in cancer and chronic HIV infection. The inhibitor of apoptosis protein antagonist Debio 1143 (D1143) enhances tumor cell death and synergizes with anti-PD-1 agents to promote tumor immunity and displayed HIV latency reversal activity in vitro. We asked in this study whether D1143 would stimulate the potency of an anti-human PD-1 monoclonal antibody (mAb) to reduce HIV loads in humanized mice. Anti-PD-1 mAb treatment decreased PD-1+ CD8+ cell population by 32.3% after interruption of four weeks treatment, and D1143 co-treatment further reduced it from 32.3 to 73%. Anti-PD-1 mAb administration reduced HIV load in blood by 94%, and addition of D1143 further enhanced this reduction from 94 to 97%. D1143 also more profoundly promoted with the anti-PD-1-mediated reduction of HIV loads in all tissues analyzed including spleen (71 to 96.4%), lymph nodes (64.3 to 80%), liver (64.2 to 94.4), lung (64.3 to 80.1%) and thymic organoid (78.2 to 98.2%), achieving a >5 log reduction of HIV loads in CD4+ cells isolated from tissues 2 weeks after drug treatment interruption. Ex vivo anti-CD3/CD28 stimulation increased the ability to activate exhausted CD8+ T cells in infected mice having received in vivo anti-PD-1 treatment by 7.9-fold (5 to 39.6%), and an additional increase by 1.7-fold upon D1143 co-treatment (39.6 to 67.3%). These findings demonstrate for the first time that an inhibitor of apoptosis protein antagonist enhances in a statistically manner the effects of an immune check point inhibitor on antiviral immunity and on HIV load reduction in tissues of humanized mice, suggesting that the combination of two distinct classes of immunomodulatory agents constitutes a promising anti-HIV immunotherapeutic approach.免疫检查点程序性死亡蛋白1（programmed cell death protein 1, PD-1）在癌症与慢性HIV感染介导的T细胞耗竭过程中发挥核心作用。凋亡蛋白抑制剂拮抗剂Debio 1143（D1143）可诱导肿瘤细胞死亡，并与抗PD-1制剂协同增强肿瘤免疫，同时在体外展现出HIV潜伏逆转活性。本研究旨在探究D1143能否提升抗人PD-1单克隆抗体（monoclonal antibody, mAb）降低人源化小鼠体内HIV载量的效能。抗PD-1单克隆抗体治疗在四周治疗中断后，可使PD-1+ CD8+细胞群体减少32.3%；而D1143联合治疗可进一步提升降幅，使该细胞群体的减少比例从32.3%升至73%。抗PD-1单克隆抗体给药可使血液中的HIV载量降低94%，联合D1143可进一步将该降幅从94%提升至97%。D1143还可更显著地促进抗PD-1介导的HIV载量降低效应，在所有分析的组织中均观察到此协同作用：脾脏（从71%提升至96.4%）、淋巴结（64.3%至80%）、肝脏（64.2%至94.4%）、肺脏（64.3%至80.1%）及胸腺类器官（78.2%至98.2%）；在药物治疗中断两周后分离的组织CD4+细胞中，实现了HIV载量大于5个对数级的降低。离体抗CD3/CD28刺激实验显示，接受过体内抗PD-1治疗的感染小鼠，其耗竭CD8+ T细胞的活化能力提升了7.9倍（从5%升至39.6%）；而联合D1143治疗可使该活化能力进一步提升1.7倍（从39.6%升至67.3%）。本研究结果首次证实，凋亡蛋白抑制剂拮抗剂可通过统计学显著的方式，增强免疫检查点抑制剂的抗病毒免疫效应及对人源化小鼠组织内HIV载量的降低作用，提示两种不同类别免疫调节制剂的联合方案是极具前景的抗HIV免疫治疗策略。