The Molecular Determinants of Antibody Recognition and Antigenic Drift in the H3 Hemagglutinin of Swine Influenza A Virus
The Molecular Determinants of Antibody Recognition and Antigenic Drift in the H3 Hemagglutinin of Swine Influenza A Virus
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DOI：
10.1128/jvi.01002-16
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发表时间：
2016-09-01
影响因子：
5.4
通讯作者：
Vincent, Amy L.
中科院分区：
文献类型：
--
作者：
Abente, Eugenio J.;Santos, Jefferson;Vincent, Amy L.
H3 亚型甲型流感病毒 (IAV) 是影响人类和猪的重要呼吸道病原体。疫苗接种诱导针对表面糖蛋白血凝素（HA）的中和抗体是控制疾病的主要方法。然而，由于抗原漂移，疫苗株必须定期更新。先前在人类季节性 H3 中鉴定的 7 个位置中的 6 个（位置 145、155、156、158、159、189 和 193）也在猪 H3 抗原进化中得到了证实。为了通过实验测试这 7 个位置对病毒抗原性的影响，将替换引入同基因猪谱系病毒的 HA 中。我们通过使用单价猪抗血清的血凝抑制（HI）数据和抗原制图来测试这些引入的取代的抗原效应，以评估突变病毒的抗原表型。抗原基序内的取代组合引起抗原性的显着变化。与野生型相比，一种病毒突变体仅在两个位置上发生变化，与同源抗血清相比，HI 滴度降低了 4 倍以上。在猪中评估了双突变体发病机制和传播的潜在变化。尽管双突变体的病毒脱落滴度和传播力与野生型相当，但它引起的肺部病变百分比却明显较低。阐明猪 H3 IAV 中这些位点的特定氨基酸取代的抗原效应对于了解猪内 IAV 的进化以及改进猪的疫苗开发和控制策略具有重要意义。 重要性流感病毒进化的一个关键组成部分是由血凝素 (HA) 蛋白中氨基酸取代的积累介导的抗原漂移，导致逃避自然感染或疫苗接种产生的先前免疫。了解 HA 的哪些氨基酸位置有助于病毒避免先前免疫的能力对于了解抗原进化很重要，并为基于当前流行毒株的基因序列数据的疫苗功效预测提供信息。继我们之前表征当代野生型猪 H3 流感病毒抗原表型的工作之后，我们通过实验验证了 HA 蛋白中 6 个氨基酸位置的取代对抗原性有重大影响。更好地了解猪流感的抗原多样性将有助于采取合理的方法选择更有效的疫苗成分来控制猪流感的传播并减少人畜共患病毒出现的可能性。
Influenza A virus (IAV) of the H3 subtype is an important respiratory pathogen that affects both humans and swine. Vaccination to induce neutralizing antibodies against the surface glycoprotein hemagglutinin (HA) is the primary method used to control disease. However, due to antigenic drift, vaccine strains must be periodically updated. Six of the 7 positions previously identified in human seasonal H3 (positions 145, 155, 156, 158, 159, 189, and 193) were also indicated in swine H3 antigenic evolution. To experimentally test the effect on virus antigenicity of these 7 positions, substitutions were introduced into the HA of an isogenic swine lineage virus. We tested the antigenic effect of these introduced substitutions by using hemagglutination inhibition (HI) data with monovalent swine antisera and antigenic cartography to evaluate the antigenic phenotype of the mutant viruses. Combinations of substitutions within the antigenic motif caused significant changes in antigenicity. One virus mutant that varied at only two positions relative to the wild type had a >4-fold reduction in HI titers compared to homologous antisera. Potential changes in pathogenesis and transmission of the double mutant were evaluated in pigs. Although the double mutant had virus shedding titers and transmissibility comparable to those of the wild type, it caused a significantly lower percentage of lung lesions. Elucidating the antigenic effects of specific amino acid substitutions at these sites in swine H3 IAV has important implications for understanding IAV evolution within pigs as well as for improved vaccine development and control strategies in swine.IMPORTANCEA key component of influenza virus evolution is antigenic drift mediated by the accumulation of amino acid substitutions in the hemagglutinin (HA) protein, resulting in escape from prior immunity generated by natural infection or vaccination. Understanding which amino acid positions of the HA contribute to the ability of the virus to avoid prior immunity is important for understanding antigenic evolution and informs vaccine efficacy predictions based on the genetic sequence data from currently circulating strains. Following our previous work characterizing antigenic phenotypes of contemporary wild-type swine H3 influenza viruses, we experimentally validated that substitutions at 6 amino acid positions in the HA protein have major effects on antigenicity. An improved understanding of the antigenic diversity of swine influenza will facilitate a rational approach for selecting more effective vaccine components to control the circulation of influenza in pigs and reduce the potential for zoonotic viruses to emerge.