A candidate HIV/AIDS vaccine (MVA-B) lacking vaccinia virus gene C6L enhances memory HIV-1-specific T-cell responses.
A candidate HIV/AIDS vaccine (MVA-B) lacking vaccinia virus gene C6L enhances memory HIV-1-specific T-cell responses.
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DOI：
10.1371/journal.pone.0024244
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发表时间：
2011
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;Tewabe N;Sorzano CO;Calandra T;Roger T;Esteban M
牛痘病毒（VACV）C6蛋白与痘病毒家族Pox_A46具有序列相似性，参与调节宿主免疫应答，但其作用尚不清楚。在这里，我们的特点是C6蛋白及其在病毒复制，先天免疫感应和免疫原性在体内的影响。C6是一种18.2 kDa的蛋白质，在病毒感染早期表达并定位于感染细胞的细胞质。从表达来自进化枝B的HIV-1 Env、Gag、Pol和Nef抗原的痘病毒载体MVA-B（MVA-B Δ C6 L）中删除C6 L基因对病毒生长动力学没有影响;因此C6蛋白对于病毒复制不是必需的。MVA-B Δ C6 L在人巨噬细胞和单核细胞来源的树突状细胞（moDC）中引发的先天性免疫信号的特征在于IFN-β和IFN-α/β诱导基因的表达上调。在小鼠的DNA初免/MVA加强免疫方案中，流式细胞术分析显示MVA-B Δ C6 L增强了HIV-1特异性CD 4+和CD 8 + T细胞记忆免疫应答的幅度和多功能性，其中大多数HIV-1应答由具有效应表型的CD 8 + T细胞区室介导。值得注意的是，虽然MVA-B优先诱导Env和Gag特异性CD 8 + T细胞应答，但MVA-B Δ C6 L诱导更多的Gag-Pol-Nef特异性CD 8 + T细胞应答。此外，MVA-B Δ C6 L与MVA-B相比，可提高抗Env抗体的水平。这些发现表明，C6可以被认为是一种免疫调节剂，并且在MVA-B中缺失C6 L基因通过增强IFN-β依赖性应答和增加针对HIV-1抗原的T细胞记忆免疫应答的幅度和质量而赋予免疫益处。我们的观察是相关的MVA载体作为HIV-1疫苗的改进。
The vaccinia virus (VACV) C6 protein has sequence similarities with the poxvirus family Pox_A46, involved in regulation of host immune responses, but its role is unknown. Here, we have characterized the C6 protein and its effects in virus replication, innate immune sensing and immunogenicity in vivo. C6 is a 18.2 kDa protein, which is expressed early during virus infection and localizes to the cytoplasm of infected cells. Deletion of the C6L gene from the poxvirus vector MVA-B expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (MVA-B ΔC6L) had no effect on virus growth kinetics; therefore C6 protein is not essential for virus replication. The innate immune signals elicited by MVA-B ΔC6L in human macrophages and monocyte-derived dendritic cells (moDCs) are characterized by the up-regulation of the expression of IFN-β and IFN-α/β-inducible genes. In a DNA prime/MVA boost immunization protocol in mice, flow cytometry analysis revealed that MVA-B ΔC6L enhanced the magnitude and polyfunctionality of the HIV-1-specific CD4+ and CD8+ T-cell memory immune responses, with most of the HIV-1 responses mediated by the CD8+ T-cell compartment with an effector phenotype. Significantly, while MVA-B induced preferentially Env- and Gag-specific CD8+ T-cell responses, MVA-B ΔC6L induced more Gag-Pol-Nef-specific CD8+ T-cell responses. Furthermore, MVA-B ΔC6L enhanced the levels of antibodies against Env in comparison with MVA-B. These findings revealed that C6 can be considered as an immunomodulator and that deleting C6L gene in MVA-B confers an immunological benefit by enhancing IFN-β-dependent responses and increasing the magnitude and quality of the T-cell memory immune responses to HIV-1 antigens. Our observations are relevant for the improvement of MVA vectors as HIV-1 vaccines.
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影响因子：
3.7
作者：
García-Arriaza J;Nájera JL;Gómez CE;Sorzano CO;Esteban M
通讯作者：
Esteban M
影响因子：
--
作者：
Aboud, Said;Nilsson, Charlotta;Godoy-Ramirez, Karina
通讯作者：
Godoy-Ramirez, Karina
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：
5.5
作者：
Elena Gomez, Carmen;Luis Najera, Jose;Esteban, Mariano
通讯作者：
Esteban, Mariano
影响因子：
64.8
作者：
Champagne, P;Ogg, GS;Pantaleo, G
通讯作者：
Pantaleo, G