Identification of Low- and High-Impact Hemagglutinin Amino Acid Substitutions That Drive Antigenic Drift of Influenza A(H1N1) Viruses.
Identification of Low- and High-Impact Hemagglutinin Amino Acid Substitutions That Drive Antigenic Drift of Influenza A(H1N1) Viruses.
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DOI：
10.1371/journal.ppat.1005526
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发表时间：
2016-04
期刊：
影响因子：
6.7
通讯作者：
Reeve R
中科院分区：
文献类型：
--
作者：
Harvey WT;Benton DJ;Gregory V;Hall JP;Daniels RS;Bedford T;Haydon DT;Hay AJ;McCauley JW;Reeve R
从遗传数据中确定表型是一个根本性的挑战。在流行的流感病毒中鉴定新出现的抗原变体对于疫苗病毒选择过程至关重要，当组分与流行病毒抗原性相似时，疫苗有效性最大化。血凝抑制（HI）试验数据通常用于评估流感抗原性。在此，分析了血凝素（HA）糖蛋白的序列和3-D结构信息以及前季节性甲型流感（H1N1）病毒分离株（1997-2009）和参考病毒的相应HI检测数据。所开发的模型识别和量化了18个氨基酸取代对HA抗原性的影响，其中两个氨基酸取代负责抗原表型的主要转变。我们使用反向遗传学来证明这些取代的一个子集对抗原性的因果影响。关于取代的影响的信息使我们能够直接从HA基因序列数据预测新出现的病毒的抗原表型，并且通过包括引起抗原变化的所有取代，准确度比仅包括具有最大影响的取代的模型提高了一倍。量化特定氨基酸取代的表型影响的能力应该有助于改进预测病毒种群从一年到下一年的演变的新兴技术，从而为候选疫苗病毒的选择提供更强的理论基础。这些技术具有很大的潜力，可以扩展到其他抗原可变的病原体。甲型流感病毒的特征是快速抗原漂移：B细胞表位的结构变化，有助于逃避预先存在的免疫力。因此，季节性流感继续对人类健康造成重大负担。准确定量特定氨基酸取代的抗原性影响是预测变异病毒适应性和进化结果的先决条件。使用测定将抗原变异归因于氨基酸序列变化，我们鉴定了导致抗原漂移的取代并量化其影响。我们发现，被鉴定为低影响的取代是病毒抗原进化的关键组成部分，通过包括这些，以及经常关注的高影响取代，从基因型预测新出现病毒的抗原表型的准确性增加了一倍。
Determining phenotype from genetic data is a fundamental challenge. Identification of emerging antigenic variants among circulating influenza viruses is critical to the vaccine virus selection process, with vaccine effectiveness maximized when constituents are antigenically similar to circulating viruses. Hemagglutination inhibition (HI) assay data are commonly used to assess influenza antigenicity. Here, sequence and 3-D structural information of hemagglutinin (HA) glycoproteins were analyzed together with corresponding HI assay data for former seasonal influenza A(H1N1) virus isolates (1997–2009) and reference viruses. The models developed identify and quantify the impact of eighteen amino acid substitutions on the antigenicity of HA, two of which were responsible for major transitions in antigenic phenotype. We used reverse genetics to demonstrate the causal effect on antigenicity for a subset of these substitutions. Information on the impact of substitutions allowed us to predict antigenic phenotypes of emerging viruses directly from HA gene sequence data and accuracy was doubled by including all substitutions causing antigenic changes over a model incorporating only the substitutions with the largest impact. The ability to quantify the phenotypic impact of specific amino acid substitutions should help refine emerging techniques that predict the evolution of virus populations from one year to the next, leading to stronger theoretical foundations for selection of candidate vaccine viruses. These techniques have great potential to be extended to other antigenically variable pathogens. Influenza A viruses are characterized by rapid antigenic drift: structural changes in B-cell epitopes that facilitate escape from pre-existing immunity. Consequently, seasonal influenza continues to impose a major burden on human health. Accurate quantification of the antigenic impact of specific amino acid substitutions is a pre-requisite for predicting the fitness and evolutionary outcome of variant viruses. Using assays to attribute antigenic variation to amino acid sequence changes we identify substitutions that contribute to antigenic drift and quantify their impact. We show that substitutions identified as low-impact are a critical component of virus antigenic evolution and by including these, as well as the high-impact substitutions often focused on, the accuracy of predicting antigenic phenotypes of emerging viruses from genotype is doubled.