Centro Nacional de Referencia para el SIDA, Universidad de Buenos Aires, Buenos Aires, Argentina.
PLoS One. 2012;7(5):e37801. doi: 10.1371/journal.pone.0037801. Epub 2012 May 24.
In Argentina, the HIV epidemic is characterized by the co-circulation of subtype B and BF recombinant viral variants. Nef is an HIV protein highly variable among subtypes, making it a good tool to study the impact of HIV variability in the vaccine design setting. We have previously reported a specific cellular response against NefBF with low cross-reactivity to NefB in mice. The aim of this work was to analyze whether the co-administration of IL-12 and GM-CSF, using DNA and MVA vaccine vectors, could improve the final cellular response induced. Mice received three DNA priming doses of a plasmid that express NefBF plus DNAs expressing IL-12 and/or GM-CSF. Afterwards, all the groups were boosted with a MVAnefBF dose. The highest increase in the magnitude of the NefBF response, compared to that induced in the control was found in the IL-12 group. Importantly, a response with higher breadth was detected in groups which received IL-12 or GM-CSF, evidenced as an increased frequency of recognition of homologous (BF) and heterologous (B) Nef peptides, as well as a higher number of other Nef peptide pools representing different viral subtypes. However, these improvements were lost when both DNA cytokines were simultaneously administered, as the response was focused against the immunodominant peptide with a detrimental response towards subdominant epitopes. The pattern of cytokines secreted and the specific-T-cell proliferative capacity were improved in IL-12 and IL-12+GM-CSF groups. Importantly IL-12 generated a significant higher T-cell avidity against a B heterologous peptide.This study indicates that the incorporation of DNA expressing IL-12 in DNA/MVA schemes produced the best results in terms of improvements of T-cell-response key properties such as breadth, cross-reactivity and quality (avidity and pattern of cytokines secreted). These relevant results contribute to the design of strategies aimed to induce T-cell responses against HIV antigens with higher quality.
在阿根廷，HIV 流行的特点是 B 亚型和 BF 重组病毒变体的共同循环。Nef 是 HIV 蛋白中高度可变的一种，使其成为研究 HIV 变异性对疫苗设计影响的良好工具。我们之前曾报道过一种针对 NefBF 的特异性细胞反应，其对 NefB 的交叉反应性较低。本工作旨在分析使用 DNA 和 MVA 疫苗载体共给予 IL-12 和 GM-CSF 是否能改善最终诱导的细胞反应。小鼠接受了三次 DNA 初始剂量的质粒，该质粒表达 NefBF 以及表达 IL-12 和/或 GM-CSF 的 DNA。之后，所有组均用 MVAnefBF 剂量加强。与对照组相比，IL-12 组 NefBF 反应的幅度增加最大。重要的是，在接受 IL-12 或 GM-CSF 的组中检测到反应广度增加，表现为识别同源（BF）和异源（B）Nef 肽的频率增加，以及更多识别不同病毒亚型的其他 Nef 肽池的频率增加。然而，当同时给予两种 DNA 细胞因子时，这些改善就会丢失，因为反应集中针对免疫显性肽，对亚显性表位产生有害反应。IL-12 和 IL-12+GM-CSF 组细胞因子分泌和特异性 T 细胞增殖能力得到改善。重要的是，IL-12 对 B 异源肽产生了更高的 T 细胞亲和力。本研究表明，在 DNA/MVA 方案中加入表达 IL-12 的 DNA 可在提高 T 细胞反应的关键特性方面产生最佳结果，例如广度、交叉反应性和质量（亲和力和细胞因子分泌模式）。这些相关结果有助于设计旨在诱导针对 HIV 抗原的更高质量 T 细胞反应的策略。
