Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
JCI Insight. 2018 Sep 20;3(18). doi: 10.1172/jci.insight.122940.
Therapeutic strategies that augment antiviral immunity and reduce the viral reservoir are critical to achieving durable remission of HIV. The coinhibitory receptor programmed death-1 (PD-1) regulates CD8+ T cell dysfunction during chronic HIV and SIV infections. We previously demonstrated that in vivo blockade of PD-1 during chronic SIV infection improves the function of antiviral CD8+ T cells and B cells. Here, we tested the immunological and virological effects of PD-1 blockade combined with antiretroviral therapy (ART) in rhesus macaques. Administration of anti-PD-1 antibody 10 days prior to ART initiation rapidly enhanced antiviral CD8+ T cell function and diminished IFN-stimulated genes. This resulted in faster viral suppression in plasma and better Th17 cell reconstitution in the rectal mucosa following ART initiation. PD-1 blockade during ART resulted in lower levels of cell-associated replication-competent virus. Following ART interruption, PD-1 antibody-treated animals showed markedly higher expansion of proliferating CXCR5+perforin+granzyme B+ effector CD8+ T cells and lower regulatory T cells that resulted in better control of viremia. Our results show that PD-1 blockade can be administered safely with ART to augment antiviral CD8+ T cell function and reduce the viral reservoir, leading to improved control of viral rebound after ART interruption.
增强抗病毒免疫和减少病毒储存库的治疗策略对于实现 HIV 的持久缓解至关重要。共抑制受体程序性死亡受体-1（PD-1）调节慢性 HIV 和 SIV 感染期间 CD8+T 细胞的功能障碍。我们之前证明，在慢性 SIV 感染期间体内阻断 PD-1 可改善抗病毒 CD8+T 细胞和 B 细胞的功能。在这里，我们测试了 PD-1 阻断联合抗逆转录病毒疗法（ART）在恒河猴中的免疫和病毒学效应。在开始 ART 之前 10 天给予抗 PD-1 抗体可迅速增强抗病毒 CD8+T 细胞的功能并减少 IFN 刺激基因。这导致在开始 ART 后更快地抑制血浆中的病毒，并更好地重建直肠黏膜中的 Th17 细胞。ART 期间的 PD-1 阻断导致细胞相关复制型病毒的水平降低。ART 中断后，接受 PD-1 抗体治疗的动物表现出明显更高的增殖性 CXCR5+穿孔素+颗粒酶 B+效应 CD8+T 细胞的扩增和较低的调节性 T 细胞，从而更好地控制病毒血症。我们的结果表明，PD-1 阻断可与 ART 一起安全地给药，以增强抗病毒 CD8+T 细胞的功能并减少病毒储存库，从而改善 ART 中断后病毒反弹的控制。
