Immunogenic profiling in mice of a HIV/AIDS vaccine candidate (MVA-B) expressing four HIV-1 antigens and potentiation by specific gene deletions.
Immunogenic profiling in mice of a HIV/AIDS vaccine candidate (MVA-B) expressing four HIV-1 antigens and potentiation by specific gene deletions.
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DOI：
10.1371/journal.pone.0012395
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发表时间：
2010-08-24
期刊：
影响因子：
3.7
通讯作者：
Esteban M
中科院分区：
文献类型：
--
作者：
García-Arriaza J;Nájera JL;Gómez CE;Sorzano CO;Esteban M
可能与预防HIV-1感染有关的HIV/AIDS候选疫苗的免疫参数仍不确定。高度减毒的痘病毒MVA株是最有希望用作HIV-1疫苗的载体之一。我们先前已经描述了表达来自进化枝B的HIV-1 Env、Gag、Pol和Nef抗原的重组MVA（称为MVA-B），其在不同动物模型中诱导HIV-1特异性免疫应答，并在具有免疫调节功能的人树突状细胞（DC）中诱导基因签名。为了更详细地表征MVA-B的免疫原性特征并改善其免疫原性，我们已经产生了一种缺乏两个基因（A41 L和B16 R）的新载体，已知这两个基因分别通过阻断CC-趋化因子和白细胞介素1β的作用来抵消宿主免疫应答（称为MVA-B Δ A41 L/Δ B16 R）。采用DNA初免/MVA加强免疫方案，比较亲本MVA-B和双缺失突变体MVA-B Δ A41 L/Δ B16 R在小鼠中诱导的适应性和记忆性HIV-1特异性免疫应答。流式细胞术分析显示，两种载体均触发HIV-1特异性CD 4+和CD 8 + T细胞，其中CD 8 + T细胞区室负责两个免疫组中总HIV-1应答的>91.9%。然而，MVA-B Δ A41 L/Δ B16 R增强了HIV-1特异性CD 4+和CD 8 + T细胞免疫应答的幅度和多功能性。在两个免疫组中，HIV-1特异性CD 4 + T细胞应答是多功能的，并且优先是Env特异性的。值得注意的是，虽然MVA-B优先诱导Env特异性CD 8 + T细胞应答，但MVA-B Δ A41 L/Δ B16 R诱导更多的GPN特异性CD 8 + T细胞应答，具有增强的多功能模式。两种载体都能够产生类似水平的抗Env抗体。这些发现表明，MVA-B和MVA-B Δ A41 L/Δ B16 R在小鼠中诱导了对HIV-1抗原的稳健、多功能和持久的T细胞应答，但双缺失突变体显示出增强的HIV-1适应性和记忆应答的幅度和质量。我们的观察结果与MVA-B的免疫评价和MVA载体作为HIV-1疫苗的改进有关。
The immune parameters of HIV/AIDS vaccine candidates that might be relevant in protection against HIV-1 infection are still undefined. The highly attenuated poxvirus strain MVA is one of the most promising vectors to be use as HIV-1 vaccine. We have previously described a recombinant MVA expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (referred as MVA-B), that induced HIV-1-specific immune responses in different animal models and gene signatures in human dendritic cells (DCs) with immunoregulatory function. In an effort to characterize in more detail the immunogenic profile of MVA-B and to improve its immunogenicity we have generated a new vector lacking two genes (A41L and B16R), known to counteract host immune responses by blocking the action of CC-chemokines and of interleukin 1β, respectively (referred as MVA-B ΔA41L/ΔB16R). A DNA prime/MVA boost immunization protocol was used to compare the adaptive and memory HIV-1 specific immune responses induced in mice by the parental MVA-B and by the double deletion mutant MVA-B ΔA41L/ΔB16R. Flow cytometry analysis revealed that both vectors triggered HIV-1-specific CD4+ and CD8+ T cells, with the CD8+ T-cell compartment responsible for >91.9% of the total HIV-1 responses in both immunization groups. However, MVA-B ΔA41L/ΔB16R enhanced the magnitude and polyfunctionality of the HIV-1-specific CD4+ and CD8+ T-cell immune responses. HIV-1-specific CD4+ T-cell responses were polyfunctional and preferentially Env-specific in both immunization groups. Significantly, while MVA-B induced preferentially Env-specific CD8+ T-cell responses, MVA-B ΔA41L/ΔB16R induced more GPN-specific CD8+ T-cell responses, with an enhanced polyfunctional pattern. Both vectors were capable of producing similar levels of antibodies against Env. These findings revealed that MVA-B and MVA-B ΔA41L/ΔB16R induced in mice robust, polyfunctional and durable T-cell responses to HIV-1 antigens, but the double deletion mutant showed enhanced magnitude and quality of HIV-1 adaptive and memory responses. Our observations are relevant in the immune evaluation of MVA-B and on improvements of MVA vectors as HIV-1 vaccines.
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影响因子：
15.3
作者：
Harari, Alexandre;Bart, Pierre-Alexandre;Stoehr, Wolfgang;Tapia, Gonzalo;Garcia, Miguel;Medjitna-Rais, Emmanuelle;Burnet, Severine;Cellerai, Cristina;Erlwein, Otto;Barber, Tristan;Moog, Christiane;Liljestrom, Peter;Wagner, Ralf;Wolf, Hans;Kraehenbuhl, Jean-Pierre;Esteban, Mariano;Heeney, Jonathan;Frachette, Marie-Joelle;Tartaglia, James;McCormack, Sheena;Babiker, Abdel;Weber, Jonathan;Pantaleo, Giuseppe
通讯作者：
Pantaleo, Giuseppe
影响因子：
4.4
作者：
Harari, A;Vallelian, F;Pantaleo, G
通讯作者：
Pantaleo, G
影响因子：
5.5
作者：
Gomez, Carmen Elena;Najera, Jose Luis;Esteban, Mariano
通讯作者：
Esteban, Mariano
影响因子：
20.3
作者：
Harari, A;Petitpierre, S;Pantaleo, G
通讯作者：
Pantaleo, G
影响因子：
64.5
作者：
ALCAMI, A;SMITH, GL
通讯作者：
SMITH, GL