Cyclophilin A as a potential genetic adjuvant to improve HIV-1 Gag DNA vaccine immunogenicity by eliciting broad and long-term Gag-specific cellular immunity in mice
Cyclophilin A as a potential genetic adjuvant to improve HIV-1 Gag DNA vaccine immunogenicity by eliciting broad and long-term Gag-specific cellular immunity in mice
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DOI：
10.1080/21645515.2015.1082692
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发表时间：
2016-02-01
影响因子：
4.8
通讯作者：
Shao, Yiming
中科院分区：
文献类型：
--
作者：
Hou, Jue;Zhang, Qicheng;Shao, Yiming
先前的研究表明，当宿主亲环蛋白A （CyPA）与HIV-1 Gag蛋白结合时，可以促进树突状细胞成熟和随后的先天免疫反应，以规避树突状细胞对HIV-1感染的抵抗。这使我们假设CyPA可能通过与Gag抗原结合来提高HIV-1 Gag特异性疫苗的免疫原性。CyPA的佐剂作用用单或双表达盒DNA疫苗进行评价。小鼠研究表明，CyPA特异性和显著促进HIV-1 gag特异性细胞免疫，但不促进HIV-1 env特异性细胞应答。Gag/CyPA双表达磁带刺激更大的Gag特异性细胞免疫应答，比单独Gag免疫。此外，CyPA诱导了广泛的gag特异性T细胞反应和持续长达5个月的强细胞免疫。此外，CyPA倾向于细胞免疫而不是体液免疫。为了研究佐剂作用的机制，对CyPA（包括活性位点残基H54Q和F60A）进行定点突变，导致在双盒中与Gag共表达的突变体。在体内分析了对该疫苗的免疫反应。有趣的是，野生型CyPA显著增加Gag细胞免疫，但H54Q和F60A突变体显著降低CyPA佐剂激活。因此，我们认为CyPA的佐剂作用是基于gag -CyPA特异性相互作用。在此，我们报道了亲环蛋白A可以作为多重DNA免疫策略中的遗传佐剂增强HIV-1 gag特异性细胞免疫，并且这种佐剂的活性是特异性的，广泛的，长期的，并且基于Gag-CyPA相互作用。
Previous research has shown that host Cyclophilin A (CyPA) can promote dendritic cell maturation and the subsequent innate immune response when incorporated into an HIV-1 Gag protein to circumvent the resistance of dendritic cells to HIV-1 infection. This led us to hypothesize that CyPA may improve HIV-1 Gag-specific vaccine immunogenicity via binding with Gag antigen. The adjuvant effect of CyPA was evaluated using a DNA vaccine with single or dual expression cassettes. Mouse studies indicated that CyPA specifically and markedly promoted HIV-1 Gag-specific cellular immunity but not an HIV-1 Env-specific cellular response. The Gag/CyPA dual expression cassettes stimulated a greater Gag-specific cellular immune response, than Gag immunization alone. Furthermore, CyPA induced a broad Gag-specific T cell response and strong cellular immunity that lasted up to 5 months. In addition, CyPA skewed to cellular rather than humoral immunity. To investigate the mechanisms of the adjuvant effect, site-directed mutagenesis in CyPA, including active site residues H54Q and F60A resulted in mutants that were co-expressed with Gag in dual cassettes. The immune response to this vaccine was analyzed in vivo. Interestingly, the wild type CyPA markedly increased Gag cellular immunity, but the H54Q and F60A mutants drastically reduced CyPA adjuvant activation. Therefore, we suggest that the adjuvant effect of CyPA was based on Gag-CyPA-specific interactions. Herein, we report that Cyclophilin A can augment HIV-1 Gag-specific cellular immunity as a genetic adjuvant in multiplex DNA immunization strategies, and that activity of this adjuvant is specific, broad, long-term, and based on Gag-CyPA interaction.