2G12-Expressing B Cell Lines May Aid in HIV Carbohydrate Vaccine Design Strategies
2G12-Expressing B Cell Lines May Aid in HIV Carbohydrate Vaccine Design Strategies
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DOI：
10.1128/jvi.02820-12
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发表时间：
2013-02-01
影响因子：
5.4
通讯作者：
Burton, Dennis R.
中科院分区：
文献类型：
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作者：
Doores, Katie J.;Huber, Michael;Burton, Dennis R.
HIV-1包膜糖蛋白gp120上高度保守的高甘露糖聚糖簇已被强调为中和抗体的靶标。2G12是第一个描述的HIV-1抗糖聚糖中和抗体，它与一个不寻常的结构域交换结构结合，产生一个高亲和力的多价结合表面。对于合理的疫苗设计来说，产生能够引发结构域交换2g12样应答的免疫原是一个有趣的挑战。我们最近发现2G12的可变结构域对二甘露糖的识别是独立于结构域交换的，但这种交换对病毒中和至关重要。以碳水化合物为基础的免疫原旨在诱导2g12样抗体，可能需要通过与B细胞受体的相互作用驱动二甘露糖识别和结构域交换。在这里，我们评估了这些免疫原激活显示域交换野生型2G12 (2G12 WT)，非域交换y型变体（2G12 I19R）和生殖系2G12 （2G12 gl）的小鼠B细胞系的能力。我们发现几种免疫原，包括热灭活酵母和细菌，可以激活2G12 WT和2G12 I19R B细胞。然而，只有离散的高甘露糖聚糖簇，如HIV-1包膜三聚体和寡突的重组形式，才能激活2G12 WT B细胞。此外，没有免疫原测试激活2g12gl细胞。我们的研究结果支持这样的假设，即为了驱动抗甘露糖抗体反应的结构域交换，需要免疫原显示传统y型抗体无法识别的离散高甘露糖聚糖簇。此外，可能还需要一种能够激活2g12gl细胞的分子。结果强调了广泛中和表达抗体的小鼠B细胞作为碳水化合物免疫原筛选的潜在有用工具。
The highly conserved cluster of high-mannose glycans on the HIV-1 envelope glycoprotein, gp120, has been highlighted as a target for neutralizing antibodies. 2G12, the first HIV-1 antiglycan neutralizing antibody described, binds with an unusual domain-exchanged structure that creates a high-affinity multivalent binding surface. It is an interesting challenge for rational vaccine design to generate immunogens capable of eliciting domain-exchanged 2G12-like responses. We recently showed that di-mannose recognition by the variable domains of 2G12 is independent of domain exchange but that exchange is critical for virus neutralization. Carbohydrate-based immunogens aimed at inducing 2G12-like antibodies may need to drive both di-mannose recognition and domain exchange through interactions with B cell receptors. Here we assessed the ability of such immunogens to activate mouse B cell lines displaying domain-exchanged wild-type 2G12 (2G12 WT), a non-domain-exchanged Y-shaped variant (2G12 I19R), and germ line 2G12 (2G12 gl). We show that several immunogens, including heat-killed yeast and bacteria, can activate both 2G12 WT and 2G12 I19R B cells. However, only discrete clusters of high-mannose glycans, as on recombinant forms of the HIV-1 envelope trimer and oligodendrons, activate 2G12 WT B cells. Furthermore, no immunogen tested activated 2G12 gl cells. Our results support the hypothesis that in order to drive domain exchange of an antimannose antibody response, a boost with an immunogen displaying discrete clusters of high-mannose glycans not recognized by conventional Y-shaped antibodies will be required. Additionally, a molecule capable of activating 2G12 gl cells might also be required. The results highlight broadly neutralizing antibody-expressing mouse B cells as potentially useful tools for carbohydrate immunogen screening.