Geometric Constraints Dominate the Antigenic Evolution of Influenza H3N2 Hemagglutinin.
Geometric Constraints Dominate the Antigenic Evolution of Influenza H3N2 Hemagglutinin.
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DOI：
10.1371/journal.ppat.1004940
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发表时间：
2015-05
期刊：
影响因子：
6.7
通讯作者：
Wilke CO
中科院分区：
文献类型：
--
作者：
Meyer AG;Wilke CO
我们对人类甲型流感H3血凝素进化的决定因素进行了全面分析。我们考虑了各个位点进化变异的三个不同预测因子：溶剂可及性（作为蛋白质折叠稳定性和/或保守性的代表）、免疫表位数据库（IEDB）表位位点（作为宿主免疫偏向的代表）和与受体结合区的接近度（作为血凝素结合唾液酸的功能之一的代表）。这些量单独解释了大约 15% 的位点 dN/dS 变化。综合起来，溶剂可及性和邻近性解释了 dN/dS 变化的 32%；将 IEDB 表位位点纳入模型仅额外增加 2 个百分点。因此，虽然溶剂可及性和邻近性在很大程度上作为进化变异的独立预测因子，但它们各自与表位位点预测因子重叠。此外，我们发现历史上的 H3 表位位点可以追溯到 20 世纪 80 年代和 1990 年代，与 IEDB 的实验位点仅部分重叠，并且当与溶剂可及性和邻近性相结合时，在预测能力上表现出类似的重叠。我们还发现，dN/dS > 1 的位点，即最有可能驱动季节性免疫逃逸的位点，不能通过历史表位位点或 IEDB 表位位点正确预测，而只能通过与受体结合区域的接近程度来正确预测。总之，HA 进化的简单几何模型优于基于表位位点的模型。这些结果表明，要么可用的表位位点不能准确代表真正的流感抗原位点，要么宿主免疫偏差对流感进化的重要性可能没有通常认为的那么重要。流感病毒是进化最快的人类病毒之一。每年，它都会积累突变，使其能够逃避先前感染个体的宿主免疫反应。病毒基因组中的哪些位点允许这种免疫逃逸以及逃逸的方式尚不完全清楚，但传统观点认为，蛋白质血凝素中的特定“免疫表位位点”优先受到宿主抗体的攻击，并且这些位点发生突变以直接避免宿主识别；因此，这些地点通常成为疫苗开发工作的目标。在这里，我们结合流感血凝素序列数据、蛋白质结构信息、IEDB免疫表位数据和历史表位来证明历史表位组和基于IEDB数据的表位对于预测流感进化速度都不是至关重要的。相反，我们发现一个简单的几何模型效果最好：最接近病毒与人类受体结合并暴露于溶剂的位置的位点是血凝素进化的主要驱动力。对于这个结果有两种可能的解释。首先，现有的历史表位和IEDB表位位点可能不是血凝素中真正的抗原位点。其次，血凝素抗原性可能不是流感进化的主要驱动力。
We have carried out a comprehensive analysis of the determinants of human influenza A H3 hemagglutinin evolution. We consider three distinct predictors of evolutionary variation at individual sites: solvent accessibility (as a proxy for protein fold stability and/or conservation), Immune Epitope Database (IEDB) epitope sites (as a proxy for host immune bias), and proximity to the receptor-binding region (as a proxy for one of the functions of hemagglutinin-to bind sialic acid). Individually, these quantities explain approximately 15% of the variation in site-wise dN/dS. In combination, solvent accessibility and proximity explain 32% of the variation in dN/dS; incorporating IEDB epitope sites into the model adds only an additional 2 percentage points. Thus, while solvent accessibility and proximity perform largely as independent predictors of evolutionary variation, they each overlap with the epitope-sites predictor. Furthermore, we find that the historical H3 epitope sites, which date back to the 1980s and 1990s, only partially overlap with the experimental sites from the IEDB, and display similar overlap in predictive power when combined with solvent accessibility and proximity. We also find that sites with dN/dS > 1, i.e., the sites most likely driving seasonal immune escape, are not correctly predicted by either historical or IEDB epitope sites, but only by proximity to the receptor-binding region. In summary, a simple geometric model of HA evolution outperforms a model based on epitope sites. These results suggest that either the available epitope sites do not accurately represent the true influenza antigenic sites or that host immune bias may be less important for influenza evolution than commonly thought. The influenza virus is one of the most rapidly evolving human viruses. Every year, it accumulates mutations that allow it to evade the host immune response of previously infected individuals. Which sites in the virus’ genome allow this immune escape and the manner of escape is not entirely understood, but conventional wisdom states that specific “immune epitope sites” in the protein hemagglutinin are preferentially attacked by host antibodies and that these sites mutate to directly avoid host recognition; as a result, these sites are commonly targeted by vaccine development efforts. Here, we combine influenza hemagglutinin sequence data, protein structural information, IEDB immune epitope data, and historical epitopes to demonstrate that neither the historical epitope groups nor epitopes based on IEDB data are crucial for predicting the rate of influenza evolution. Instead, we find that a simple geometrical model works best: sites that are closest to the location where the virus binds the human receptor and are exposed to solvent are the primary drivers of hemagglutinin evolution. There are two possible explanations for this result. First, the existing historical and IEDB epitope sites may not be the real antigenic sites in hemagglutinin. Second, alternatively, hemagglutinin antigenicity may not be the primary driver of influenza evolution.
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DOI：
10.1084/jem.20130212
发表时间：
2013-07-29
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Li Y;Myers JL;Bostick DL;Sullivan CB;Madara J;Linderman SL;Liu Q;Carter DM;Wrammert J;Esposito S;Principi N;Plotkin JB;Ross TM;Ahmed R;Wilson PC;Hensley SE
通讯作者：
Hensley SE
影响因子：
56.9
作者：
Kim, Philip M.;Lu, Long J.;Gerstein, Mark B.
通讯作者：
Gerstein, Mark B.
影响因子：
10.7
作者：
Bhatt, Samir;Holmes, Edward C.;Pybus, Oliver G.
通讯作者：
Pybus, Oliver G.
影响因子：
10.7
作者：
Katoh K;Standley DM
通讯作者：
Standley DM
影响因子：
5.6
作者：
Lichtarge, O;Bourne, HR;Cohen, FE
通讯作者：
Cohen, FE