Liu Fengliang, Niu Qingli, Fan Xiuzhen, Liu Connie, Zhang Jie, Wei Zhi, Hou Wei, Kanneganti Thirumala-Devi, Robb Merlin L, Kim Jerome H, Michael Nelson L, Sun Jiaren, Soong Lynn, Hu Haitao
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555.
Department of Computer Science, New Jersey Institute of Technology, Newark, NJ 07102.
J Immunol. 2017 Nov 1;199(9):3293-3305. doi: 10.4049/jimmunol.1700698. Epub 2017 Sep 25.
Viral vectors derived from different virus families, including poxvirus (canarypox virus vector ALVAC) and adenovirus (human Ad5 vector), have been widely used in vaccine development for a range of human diseases including HIV/AIDS. Less is known about the mechanisms underlying the host innate response to these vectors. Increasing evidence from clinical vaccine trials testing different viral vectors has suggested the importance of understanding basic elements of host-viral vector interactions. In this study, we investigated the innate interactions of APCs with two commonly used HIV vaccine vectors, ALVAC and Ad5, and identified AIM2 as an innate sensor for ALVAC, triggering strong inflammasome activation in both human and mouse APCs. Microarray and comprehensive gene-knockout analyses (CRISPR/Cas9) identified that ALVAC stimulated the cGAS/IFI16-STING-type I IFN pathway to prime AIM2, which was functionally required for ALVAC-induced inflammasome activation. We also provided evidence that, in contrast to ALVAC, the Ad5 vector itself was unable to induce inflammasome activation, which was related to its inability to stimulate the STING-type I IFN pathway and to provide inflammasome-priming signals. In preconditioned APCs, the Ad5 vector could stimulate inflammasome activation through an AIM2-independent mechanism. Therefore, our study identifies the AIM2 inflammasome and cGAS/IFI16-STING-type I IFN pathway as a novel mechanism for host innate immunity to the ALVAC vaccine vector.
源自不同病毒家族的病毒载体,包括痘病毒(金丝雀痘病毒载体ALVAC)和腺病毒(人Ad5载体),已广泛用于包括HIV/AIDS在内的一系列人类疾病的疫苗开发。关于宿主对这些载体的先天反应的潜在机制,人们了解较少。来自测试不同病毒载体的临床疫苗试验的证据越来越多,表明了解宿主-病毒载体相互作用的基本要素很重要。在本研究中,我们研究了抗原呈递细胞(APC)与两种常用的HIV疫苗载体ALVAC和Ad5的先天相互作用,并确定AIM2是ALVAC的一种先天传感器,可在人和小鼠APC中触发强烈的炎性小体激活。微阵列和全面的基因敲除分析(CRISPR/Cas9)确定,ALVAC刺激cGAS/IFI16-STING-I型干扰素途径来启动AIM2,这是ALVAC诱导的炎性小体激活在功能上所必需的。我们还提供了证据表明,与ALVAC不同,Ad5载体本身无法诱导炎性小体激活,这与其无法刺激STING-I型干扰素途径并提供炎性小体启动信号有关。在预处理的APC中,Ad5载体可通过一种不依赖AIM2的机制刺激炎性小体激活。因此,我们的研究确定AIM2炎性小体和cGAS/IFI16-STING-I型干扰素途径是宿主对ALVAC疫苗载体先天免疫的一种新机制。