Co-expression of miRNA targeting the expression of PERK, but not PKR, enhances cellular immunity from an HIV-1 Env DNA vaccine.
Co-expression of miRNA targeting the expression of PERK, but not PKR, enhances cellular immunity from an HIV-1 Env DNA vaccine.
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DOI：
10.1371/journal.pone.0018225
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发表时间：
2011-03-25
期刊：
影响因子：
3.7
通讯作者：
Purcell DF
中科院分区：
文献类型：
--
作者：
Wheatley AK;Kramski M;Alexander MR;Toe JG;Center RJ;Purcell DF
小的非编码微RNA（miRNA）是哺乳动物基因表达的重要转录后调节因子，其可用于指导靶基因的表达敲低。我们研究了共表达miRNA与HIV-1包膜（Env）抗原的DNA疫苗载体是否会影响小鼠对Env的免疫应答的幅度或质量。将人miR-155和来自非蛋白质编码基因mirhg 155的侧翼区引入HIV-1 Env gp 140表达载体内的人工内含子中。使用miR-155表达内含子作为支架，我们开发了用于miRNA介导的靶向细胞抗病毒蛋白PKR和PERK的新型载体，其显著下调靶基因表达并导致体外Env表达增加。最后，用递送靶向PERK而非PKR的miRNA的DNA疫苗载体接种BALB/c小鼠能够增加Env特异性T细胞免疫的产生。这项研究提供了概念验证的证据，即miRNA效应子纳入疫苗构建体可以积极影响疫苗的免疫原性。对疫苗编码的miRNA的进一步测试将确定这些策略是否可以增强针对HIV-1的疫苗的保护效力，以最终用于人类。
Small non-coding micro-RNAs (miRNA) are important post-transcriptional regulators of mammalian gene expression that can be used to direct the knockdown of expression from targeted genes. We examined whether DNA vaccine vectors co-expressing miRNA with HIV-1 envelope (Env) antigens could influence the magnitude or quality of the immune responses to Env in mice. Human miR-155 and flanking regions from the non-protein encoding gene mirhg155 were introduced into an artificial intron within an expression vector for HIV-1 Env gp140. Using the miR-155-expressing intron as a scaffold, we developed novel vectors for miRNA-mediated targeting of the cellular antiviral proteins PKR and PERK, which significantly down-modulated target gene expression and led to increased Env expression in vitro. Finally, vaccinating BALB/c mice with a DNA vaccine vector delivering miRNA targeting PERK, but not PKR, was able to augment the generation of Env-specific T-cell immunity. This study provides proof-of-concept evidence that miRNA effectors incorporated into vaccine constructs can positively influence vaccine immunogenicity. Further testing of vaccine-encoded miRNA will determine if such strategies can enhance protective efficacy from vaccines against HIV-1 for eventual human use.
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