Centro Nacional de Referencia para el SIDA, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
PLoS One. 2012;7(2):e32220. doi: 10.1371/journal.pone.0032220. Epub 2012 Feb 22.
Modified Vaccinia Ankara (MVA) is an attenuated strain of Vaccinia virus (VACV) currently employed in many clinical trials against HIV/AIDS and other diseases. MVA still retains genes involved in host immune response evasion, enabling its optimization by removing some of them. The aim of this study was to evaluate cellular immune responses (CIR) induced by an IL-18 binding protein gene (C12L) deleted vector (MVAΔC12L).
METHODOLOGY/PRINCIPAL FINDINGS: BALB/c and C57BL/6 mice were immunized with different doses of MVAΔC12L or MVA wild type (MVAwt), then CIR to VACV epitopes in immunogenic proteins were evaluated in spleen and draining lymph nodes at acute and memory phases (7 and 40 days post-immunization respectively). Compared with parental MVAwt, MVAΔC12L immunization induced a significant increase of two to three-fold in CD8(+) and CD4(+) T-cell responses to different VACV epitopes, with increased percentage of anti-VACV cytotoxic CD8(+) T-cells (CD107a/b(+)) during the acute phase of the response. Importantly, the immunogenicity enhancement was also observed after MVAΔC12L inoculation with different viral doses and by distinct routes (systemic and mucosal). Potentiation of MVA's CIR was also observed during the memory phase, in correlation with a higher protection against an intranasal challenge with VACV WR. Of note, we could also show a significant increase in the CIR against HIV antigens such as Env, Gag, Pol and Nef from different subtypes expressed from two recombinants of MVAΔC12L during heterologous DNA prime/MVA boost vaccination regimens.
CONCLUSIONS/SIGNIFICANCE: This study demonstrates the relevance of IL-18 bp contribution in the immune response evasion during MVA infection. Our findings clearly show that the deletion of the viral IL-18 bp gene is an effective approach to increase MVA vaccine efficacy, as immunogenicity improvements were observed against vector antigens and more importantly to HIV antigens.
改良安卡拉痘苗病毒（MVA）是一种减毒的痘苗病毒（VACV）株，目前被广泛应用于许多针对 HIV/AIDS 和其他疾病的临床试验中。MVA 仍然保留了一些与宿主免疫反应逃避有关的基因，这使得通过删除其中的一些基因来对其进行优化成为可能。本研究旨在评估缺失白细胞介素 18 结合蛋白基因（C12L）的载体（MVAΔC12L）诱导的细胞免疫反应（CIR）。
方法/主要发现：BALB/c 和 C57BL/6 小鼠分别用不同剂量的 MVAΔC12L 或野生型 MVA（MVAwt）进行免疫接种，然后在急性和记忆阶段（分别为免疫接种后 7 天和 40 天）评估对免疫原性蛋白中 VACV 表位的 CIR。与亲本 MVAwt 相比，MVAΔC12L 免疫接种可使针对不同 VACV 表位的 CD8+和 CD4+T 细胞反应增加两到三倍，并且在急性反应期间增加了抗 VACV 细胞毒性 CD8+T 细胞（CD107a/b+）的百分比。重要的是，在用不同病毒剂量和不同途径（全身和黏膜）接种 MVAΔC12L 后，也观察到了免疫原性增强。在记忆阶段，MVA 的 CIR 也得到了增强，与用 VACV WR 进行鼻腔内攻击的更高保护率相关。值得注意的是，我们还可以观察到，在用 MVAΔC12L 的两种重组体进行异源 DNA 初免/MVA 加强免疫接种方案后，针对来自不同亚型的 HIV 抗原（如Env、Gag、Pol 和 Nef）的 CIR 也显著增加。
结论/意义：本研究证明了白细胞介素 18 结合蛋白在 MVA 感染期间免疫反应逃避中的相关性。我们的研究结果清楚地表明，删除病毒白细胞介素 18 结合蛋白基因是提高 MVA 疫苗效力的有效方法，因为针对载体抗原和更重要的是针对 HIV 抗原的免疫原性得到了改善。
