Novel HIV IL-4R antagonist vaccine strategy can induce both high avidity CD8 T and B cell immunity with greater protective efficacy
Novel HIV IL-4R antagonist vaccine strategy can induce both high avidity CD8 T and B cell immunity with greater protective efficacy
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DOI：
10.1016/j.vaccine.2014.08.023
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发表时间：
2014-09-29
期刊：
影响因子：
5.5
通讯作者：
Ranasinghe, Charani
中科院分区：
文献类型：
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作者：
Jackson, Ronald J.;Worley, Matthew;Ranasinghe, Charani
我们已经确定，异源痘病毒载体 HIV 疫苗（鸡痘病毒 (FPV)-HIV gag/pol prime 和减毒牛痘病毒 (VV)-HIV gag/pol 加强免疫接种）的功效受到初免疫苗接种部位细胞因子环境的强烈影响，内源性 IL-13 不利于诱导的 HIV 特异性 CD8+ T 细胞反应的质量。我们现在开发了一种新型 HIV 疫苗，它共表达小鼠 IL-4 的 C 端缺失突变体，删除了信号传导所需的必需酪氨酸 (Y119)。在我们的疫苗系统中，突变体IL-4C118可以高亲和力与IL-4 I型和II型受体结合，并暂时阻止疫苗接种部位IL-4和IL-13的信号传导。当这种 IL-4C118 佐剂疫苗用于鼻内 rFPV/肌内 rVV 初免加强免疫策略时，检测到粘膜/全身 HIV 特异性 CD8+ T 细胞具有更高的功能亲和力，表达 IFN-γ、TNF-α 和 IL-2，并且检测到更大的保护功效。令人惊讶的是，IL-4C118 佐剂疫苗还诱导了强烈的长效 HIV gag 特异性血清抗体反应，特别是 IgG1 和 IgG2a。诱导的 p55-gag IgG2a 反应相对于 IL-13R α 2 佐剂疫苗具有更高的强度。更有趣的是，我们最近测试的 IL-13R α2 佐剂疫苗仅抑制 IL-13 活性，尽管诱导了优异的高亲合力 HIV 特异性 CD8+ T 细胞，但对 gag 特异性 IgG2a 抗体免疫的诱导产生了不利影响。我们的观察结果表明，(i) 在没有 IL-13 的情况下，IL-4 细胞信号传导延迟了 gag 特异性抗体同种型类别转换，或 (ii) IL-13R α 2 信号传导参与诱导良好的 gag 特异性 B 细胞免疫。因此，我们相信我们的新型 IL-4R 拮抗剂佐剂策略不仅为 HIV-1 疫苗提供了巨大的希望，而且还为对抗一系列需要持续高质量粘膜和全身 T 和 B 细胞免疫来保护的慢性感染提供了广阔的前景。 (C) 2014 年作者。由 Elsevier Ltd 出版。这是一篇遵循 CC BY-NC-ND 许可证 (http://creativecommons.org/licenses/by-nc-nd/3.0/) 的开放获取文章。
We have established that the efficacy of a heterologous poxvirus vectored HIV vaccine, fowlpox virus (FPV)-HIV gag/pol prime followed by attenuated vaccinia virus (VV)-HIV gag/pol booster immunisation, is strongly influenced by the cytokine milieu at the priming vaccination site, with endogenous IL-13 detrimental to the quality of the HIV specific CD8+ T cell response induced. We have now developed a novel HIV vaccine that co-expresses a C-terminal deletion mutant of the mouse IL-4, deleted for the essential tyrosine (Y119) required for signalling. In our vaccine system, the mutant IL-4C118 can bind to IL-4 type I and II receptors with high affinity, and transiently prevent the signalling of both IL-4 and IL-13 at the vaccination site. When this IL-4C118 adjuvanted vaccine was used in an intranasal rFPV/intramuscular rVV prime-boost immunisation strategy, greatly enhanced mucosal/systemic HIV specific CD8+ T cells with higher functional avidity, expressing IFN-gamma, TNF-alpha and IL-2 and greater protective efficacy were detected. Surprisingly, the IL-4C118 adjuvanted vaccines also induced robust long-lived HIV gag-specific serum antibody responses, specifically IgG1 and IgG2a. The p55-gag IgG2a responses induced were of a higher magnitude relative to the IL-13R alpha 2 adjuvant vaccine. More interestingly, our recently tested IL-13R alpha 2 adjuvanted vaccine which only inhibited IL-13 activity, even though induced excellent high avidity HIV-specific CD8+ T cells, had a detrimental impact on the induction of gag-specific IgG2a antibody immunity. Our observations suggest that (i) IL-4 cell-signalling in the absence of IL-13 retarded gag-specific antibody isotype class switching, or (ii) IL-13R alpha 2 signalling was involved in inducing good gag-specific B cell immunity. Thus, we believe our novel IL-4R antagonist adjuvant strategy offers great promise not only for HIV-1 vaccines, but also against a range of chronic infections where sustained high quality mucosal and systemic T and B cell immunity are required for protection. (C) 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).