Chimeric HIV-1 envelope glycoproteins with potent intrinsic granulocyte-macrophage colony-stimulating factor (GM-CSF) activity.
Chimeric HIV-1 envelope glycoproteins with potent intrinsic granulocyte-macrophage colony-stimulating factor (GM-CSF) activity.
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DOI：
10.1371/journal.pone.0060126
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sanders RW
中科院分区：
文献类型：
--
作者：
Isik G;van Montfort T;Boot M;Cobos Jiménez V;Kootstra NA;Sanders RW
HIV-1的获得可以通过靶向包膜糖蛋白复合物（Env）的广泛中和抗体（brnab）来阻止。因此，理想的疫苗应该能够诱导能够长时间提供免疫的brnab，但HIV-1 Env的低内在免疫原性使得这种brnab的激发具有挑战性。共刺激分子可以增加Env的免疫原性，我们设计了一种可溶性嵌合Env三聚体，其嵌入了粒细胞-巨噬细胞集落刺激因子（GM-CSF）结构域。与不含GM-CSF的Env相比，这种嵌合分子诱导小鼠B细胞和辅助性T细胞反应增强。我们研究了是否可以优化嵌入的GM-CSF的活性以及嵌合分子的Env成分的抗原结构。我们评估了截断GM-CSF、去除GM-CSF中的糖基化位点以及调整GM-CSF与Env之间的连接长度的效果。我们设计的一个EnvGM-CSF嵌合体将GM-CSF依赖性细胞的增殖能力提高了6倍，达到与可溶性重组GM-CSF相同的活性。此外，我们将GM-CSF纳入可切割的Env三聚体中，发现GM-CSF的插入不会影响Env的切割，而Env的切割也不会影响GM-CSF的活性。重要的是，这些优化的EnvGM-CSF蛋白能够将人单核细胞分化为具有巨噬细胞样表型的细胞。嵌合EnvGM-CSF应该有助于改善针对HIV-1的体液免疫，这些研究应该为其他嵌合蛋白的设计提供信息。
HIV-1 acquisition can be prevented by broadly neutralizing antibodies (BrNAbs) that target the envelope glycoprotein complex (Env). An ideal vaccine should therefore be able to induce BrNAbs that can provide immunity over a prolonged period of time, but the low intrinsic immunogenicity of HIV-1 Env makes the elicitation of such BrNAbs challenging. Co-stimulatory molecules can increase the immunogenicity of Env and we have engineered a soluble chimeric Env trimer with an embedded granulocyte-macrophage colony-stimulating factor (GM-CSF) domain. This chimeric molecule induced enhanced B and helper T cell responses in mice compared to Env without GM-CSF. We studied whether we could optimize the activity of the embedded GM-CSF as well as the antigenic structure of the Env component of the chimeric molecule. We assessed the effect of truncating GM-CSF, removing glycosylation-sites in GM-CSF, and adjusting the linker length between GM-CSF and Env. One of our designed EnvGM-CSF chimeras improved GM-CSF-dependent cell proliferation by 6-fold, reaching the same activity as soluble recombinant GM-CSF. In addition, we incorporated GM-CSF into a cleavable Env trimer and found that insertion of GM-CSF did not compromise Env cleavage, while Env cleavage did not compromise GM-CSF activity. Importantly, these optimized EnvGM-CSF proteins were able to differentiate human monocytes into cells with a macrophage-like phenotype. Chimeric EnvGM-CSF should be useful for improving humoral immunity against HIV-1 and these studies should inform the design of other chimeric proteins.
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影响因子：
3.7
作者：
Eggink, Dirk;Melchers, Mark;Sanders, Rogier W.
通讯作者：
Sanders, Rogier W.
影响因子：
1.8
作者：
JUST, U;FRIEL, J;OSTERTAG, W
通讯作者：
OSTERTAG, W
HIV-1 疫苗功效试验的免疫相关分析。
DOI：
10.1056/nejmoa1113425
发表时间：
2012-04-05
期刊：
The New England journal of medicine
影响因子：
--
作者：
Haynes BF;Gilbert PB;McElrath MJ;Zolla-Pazner S;Tomaras GD;Alam SM;Evans DT;Montefiori DC;Karnasuta C;Sutthent R;Liao HX;DeVico AL;Lewis GK;Williams C;Pinter A;Fong Y;Janes H;DeCamp A;Huang Y;Rao M;Billings E;Karasavvas N;Robb ML;Ngauy V;de Souza MS;Paris R;Ferrari G;Bailer RT;Soderberg KA;Andrews C;Berman PW;Frahm N;De Rosa SC;Alpert MD;Yates NL;Shen X;Koup RA;Pitisuttithum P;Kaewkungwal J;Nitayaphan S;Rerks-Ngarm S;Michael NL;Kim JH
通讯作者：
Kim JH
影响因子：
5.4
作者：
Binley, JM;Sanders, RW;Moore, JP
通讯作者：
Moore, JP
影响因子：
30.5
作者：
Kwong, Peter D.;Wilson, Ian A.
通讯作者：
Wilson, Ian A.