A nonself sugar mimic of the HIV glycan shield shows enhanced antigenicity
A nonself sugar mimic of the HIV glycan shield shows enhanced antigenicity
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DOI：
10.1073/pnas.1002717107
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发表时间：
2010-10-05
影响因子：
11.1
通讯作者：
Davis, Benjamin G.
中科院分区：
文献类型：
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作者：
Doores, Katie J.;Fulton, Zara;Davis, Benjamin G.
抗体2G12通过结合HIV-1表面糖蛋白gp120上的高甘露糖聚糖，独特地中和了广泛的HIV-1分离物。类似于这些2G12天然表位的抗原将是HIV-1疫苗非常理想的成分。然而，到目前为止，宿主产生的（自身）碳水化合物基序尚未成功引发与gp120交叉反应的2g12样抗体。基于令人惊讶的观察，2G12结合非蛋白单糖d -果糖比d -甘露糖具有更高的亲和力，我们在这里展示了一组设计的非自身合成单糖是有效的抗原。当被引入到被2G12识别的蛋白聚糖的D1臂末端时，它们的抗原性显著增强。这些非天然糖的逻辑变异确定了关键修饰，并利用高分辨率晶体学分析阐明了这种增加的抗原性的分子基础。含有这种非自身聚糖的病毒样颗粒蛋白偶联物与2G12结合更紧密。作为免疫原，它们比含有自身D1聚糖基序的免疫原偶联物产生更高的抗体滴度。这些由非自身免疫原产生的抗体，当它出现在一系列不同的偶联物和聚糖中时，也会与这个在聚糖屏蔽中发现的自我基序发生交叉反应。然而，当存在于gp120上时，这些抗体不能结合这个聚糖基序。
Antibody 2G12 uniquely neutralizes a broad range of HIV-1 isolates by binding the high-mannose glycans on the HIV-1 surface glycoprotein, gp120. Antigens that resemble these natural epitopes of 2G12 would be highly desirable components for an HIV-1 vaccine. However, host-produced (self)-carbohydrate motifs have been unsuccessful so far at eliciting 2G12-like antibodies that cross-react with gp120. Based on the surprising observation that 2G12 binds nonproteinaceous monosaccharide D-fructose with higher affinity than D-mannose, we show here that a designed set of nonself, synthetic monosaccharides are potent antigens. When introduced to the terminus of the D1 arm of protein glycans recognized by 2G12, their antigenicity is significantly enhanced. Logical variation of these unnatural sugars pinpointed key modifications, and the molecular basis of this increased antigenicity was elucidated using high-resolution crystallographic analyses. Virus-like particle protein conjugates containing such nonself glycans are bound more tightly by 2G12. As immunogens they elicit higher titers of antibodies than those immunogenic conjugates containing the self D1 glycan motif. These antibodies generated from nonself immunogens also cross-react with this self motif, which is found in the glycan shield, when it is presented in a range of different conjugates and glycans. However, these antibodies did not bind this glycan motif when present on gp120.