Aroh Chukwuemika, Wang Zhaohui, Dobbs Nicole, Luo Min, Chen Zhijian, Gao Jinming, Yan Nan
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390.
J Immunol. 2017 Dec 1;199(11):3840-3848. doi: 10.4049/jimmunol.1700972. Epub 2017 Oct 30.
HIV-1 evades immune detection by the cGAS-STING cytosolic DNA-sensing pathway during acute infection. STING is a critical mediator of type I IFN production, and STING agonists such as cGMP-AMP (cGAMP) and other cyclic dinucleotides elicit potent immune and antitumor response. In this article, we show that administration of cGAMP, delivered by an ultra-pH-sensitive nanoparticle (NP; PC7A), in human PBMCs induces potent and long-acting antiretroviral response against several laboratory-adapted and clinical HIV-1 isolates. cGAMP-PC7A NP requires endocytosis for intracellular delivery and immune signaling activation. cGAMP-PC7A NP-induced protection is mediated through type I IFN signaling and requires monocytes in PBMCs. cGAMP-PC7A NPs also inhibit HIV-1 replication in HIV patient PBMCs after ex vivo reactivation. Because pattern recognition receptor agonists continue to show more clinical benefits than the traditional IFN therapy, our data present important evidence for potentially developing cGAMP or other STING agonists as a new class of immune-stimulating long-acting antiretroviral agents.
在急性感染期间，HIV-1通过cGAS-STING胞质DNA感应途径逃避免疫检测。STING是I型干扰素产生的关键介质，而STING激动剂如cGMP-AMP（cGAMP）和其他环二核苷酸可引发强大的免疫和抗肿瘤反应。在本文中，我们表明，通过超pH敏感纳米颗粒（NP；PC7A）递送的cGAMP在人外周血单个核细胞（PBMC）中可诱导针对几种实验室适应株和临床HIV-1分离株的强大且长效的抗逆转录病毒反应。cGAMP-PC7A纳米颗粒需要内吞作用来进行细胞内递送和免疫信号激活。cGAMP-PC7A纳米颗粒诱导的保护作用是通过I型干扰素信号介导的，并且需要PBMC中的单核细胞。cGAMP-PC7A纳米颗粒在体外重新激活后也能抑制HIV患者PBMC中的HIV-1复制。由于模式识别受体激动剂继续显示出比传统干扰素疗法更多的临床益处，我们的数据为潜在开发cGAMP或其他STING激动剂作为一类新型免疫刺激长效抗逆转录病毒药物提供了重要证据。
