Structural basis of differential neutralization of DENV-1 genotypes by an antibody that recognizes a cryptic epitope.
Structural basis of differential neutralization of DENV-1 genotypes by an antibody that recognizes a cryptic epitope.
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DOI：
10.1371/journal.ppat.1002930
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Fremont DH
中科院分区：
文献类型：
--
作者：
Austin SK;Dowd KA;Shrestha B;Nelson CA;Edeling MA;Johnson S;Pierson TC;Diamond MS;Fremont DH
我们先前开发了一组针对登革热病毒（DENV）-1的中和性单克隆抗体，其中很少有对所有DENV - 1基因型都表现出抑制活性的。这一发现与观察到使用自然感染或免疫个体的血清对不同DENV毒株和基因型进行可变中和的报告一致。在此，我们描述了DENV1 - E111与来自两种不同DENV - 1基因型的E蛋白结构域III（DIII）上一个新的CC′环表位结合的晶体结构。将我们的结构与现有的DENV病毒粒子冷冻电镜模型进行对接显示，DENV1 - E111表位无法接近，这表明该抗体识别一种未被表征的病毒构象。虽然DENV1 - E111与DIII之间的结合亲和力因基因型而异，但我们观察到与抑制活性的相关性有限。相反，我们的结果支持这样的结论：有效的中和作用取决于CC′环表位的基因型依赖性暴露。这些发现确立了DENV病毒粒子新的结构复杂性，这可能与在疫苗开发背景下选择DENV毒株用于诱导或分析中和抗体有关。
在每种登革热病毒（DENV）血清型内，病毒根据蛋白质序列变异被细分为基因型。据信，感染某一给定血清型会诱导产生中和抗体，这些抗体对同一血清型的毒株的二次感染提供长期免疫力。然而，近期研究表明，某些种类的中和抗体不能对DENV血清型内的所有基因型同等地抑制感染。DENV1 - E111是一种对DENV - 1毒株感染有差异中和作用的抗体的例子。我们使用结构和分子方法确定DENV1 - E111与包膜蛋白结构域III中的一个表位结合。尽管DENV - 1基因型之间表位序列存在差异，但当我们在基因型之间交换表位内的氨基酸时，抗体的抑制活性仍然不相等。将我们的结构与DENV病毒粒子模型对接显示，DENV1 - E111表位无法接近，这表明抗体识别一种未被表征的病毒构象。我们的研究表明，DENV病毒粒子结构以基因型依赖的方式存在差异，这可能影响识别隐蔽表位的抗体的抑制活性。
We previously developed a panel of neutralizing monoclonal antibodies against Dengue virus (DENV)-1, of which few exhibited inhibitory activity against all DENV-1 genotypes. This finding is consistent with reports observing variable neutralization of different DENV strains and genotypes using serum from individuals that experienced natural infection or immunization. Herein, we describe the crystal structures of DENV1-E111 bound to a novel CC′ loop epitope on domain III (DIII) of the E protein from two different DENV-1 genotypes. Docking of our structure onto the available cryo-electron microscopy models of DENV virions revealed that the DENV1-E111 epitope was inaccessible, suggesting that this antibody recognizes an uncharacterized virus conformation. While the affinity of binding between DENV1-E111 and DIII varied by genotype, we observed limited correlation with inhibitory activity. Instead, our results support the conclusion that potent neutralization depends on genotype-dependent exposure of the CC′ loop epitope. These findings establish new structural complexity of the DENV virion, which may be relevant for the choice of DENV strain for induction or analysis of neutralizing antibodies in the context of vaccine development. Within each Dengue virus (DENV) serotype, viruses are subdivided into genotypes based upon the protein sequence variation. Infection with a given serotype is believed to induce neutralizing antibodies that provide long-term immunity against secondary infection by a strain of the same serotype. However, recent studies suggest that some classes of neutralizing antibodies fail to inhibit infection equivalently for all genotypes within a DENV serotype. DENV1-E111 is an example of an antibody that differentially neutralizes infection of DENV-1 strains. We used structural and molecular approaches to determine that DENV1-E111 binds to an epitope in domain III of the envelope protein. Although the epitope sequence varied between DENV-1 genotypes, inhibitory activity of the antibody remained unequal when we exchanged the amino acids within the epitope among genotypes. Docking of our structures onto DENV virion models revealed that the DENV1-E111 epitope was inaccessible, suggesting that the antibody recognizes an uncharacterized virus conformation. Our studies suggest that DENV virion structures differ in a genotype-dependent manner, which can impact the inhibitory activity of antibodies that recognize cryptic epitopes.
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影响因子：
6.7
作者：
Balsitis SJ;Williams KL;Lachica R;Flores D;Kyle JL;Mehlhop E;Johnson S;Diamond MS;Beatty PR;Harris E
通讯作者：
Harris E
DOI：
10.1073/pnas.0703498104
发表时间：
2007-05-29
影响因子：
11.1
作者：
Goncalvez, Ana P.;Engle, Ronald E.;Lai, Ching-Juh
通讯作者：
Lai, Ching-Juh
影响因子：
11.4
作者：
Cockburn, Joseph J. B.;Sanchez, M. Erika Navarro;Rey, Felix A.
通讯作者：
Rey, Felix A.
影响因子：
30.3
作者：
Beltramello M;Williams KL;Simmons CP;Macagno A;Simonelli L;Quyen NT;Sukupolvi-Petty S;Navarro-Sanchez E;Young PR;de Silva AM;Rey FA;Varani L;Whitehead SS;Diamond MS;Harris E;Lanzavecchia A;Sallusto F
通讯作者：
Sallusto F
影响因子：
12.7
作者：
Alvarez, Mayling;Pavon-Oro, Alequis;Guzman, Maria G.
通讯作者：
Guzman, Maria G.