The influenza virus hemagglutinin head evolves faster than the stalk domain.
The influenza virus hemagglutinin head evolves faster than the stalk domain.
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DOI：
10.1038/s41598-018-28706-1
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发表时间：
2018-07-11
影响因子：
4.6
通讯作者：
Krammer F
中科院分区：
文献类型：
--
作者：
Kirkpatrick E;Qiu X;Wilson PC;Bahl J;Krammer F
目前的流感病毒疫苗预防抗原漂移或转移病毒的能力有限，造成了公共卫生问题，因此需要开发有效的、具有广泛保护性的疫苗。虽然目前的流感病毒疫苗主要诱导针对血凝素（病毒的主要表面糖蛋白）的免疫显性和可变头结构域的免疫反应，但血凝素茎结构域已被确定含有中和 B 细胞表位，这些表位在甲型流感病毒亚型之间甚至在甲型流感病毒亚型之间是保守的。目前还缺乏对当前疫苗的主要靶标和这个更保守的茎区域之间进化差异的完整了解。在这里，我们对大流行前季节性 H1N1、大流行 H1N1、季节性 H3N2 和乙型流感病毒的血凝素的茎结构域进行了进化分析，并首次定量显示茎结构域的进化速度明显慢于头结构域。此外，我们发现与蛋白质的整个头部和茎部区域相比，广泛中和单克隆抗体靶向的茎部结构域中的交叉反应表位的进化速度甚至更慢。最后，对这些病毒组的头部和茎部区域进行了固定效应似然选择分析。虽然在头域中发现了几个正选择位点，但在大流行前季节性 H1 血凝素的茎域中仅在氨基酸位置 468（从蛋氨酸开始的 H1 编号）处识别出一个位点。该位点不位于或不靠近交叉反应性抗茎单克隆抗体的表位。此外，我们发现该位点的变化不会显着影响人类抗茎抗体的病毒结合或中和，这表明茎结构域中的一些正选择与免疫压力无关。我们的结论是，虽然茎结构域确实随着时间的推移而进化，但这种进化是缓慢的，并且从历史上看，并不是为了帮助逃避中和抗体反应。
The limited ability of current influenza virus vaccines to protect from antigenically drifted or shifted viruses creates a public health problem that has led to the need to develop effective, broadly protective vaccines. While current influenza virus vaccines mostly induce an immune response against the immunodominant and variable head domain of the hemagglutinin, the major surface glycoprotein of the virus, the hemagglutinin stalk domain has been identified to harbor neutralizing B-cell epitopes that are conserved among and even between influenza A virus subtypes. A complete understanding of the differences in evolution between the main target of current vaccines and this more conserved stalk region are missing. Here, we performed an evolutionary analysis of the stalk domains of the hemagglutinin of pre-pandemic seasonal H1N1, pandemic H1N1, seasonal H3N2, and influenza B viruses and show quantitatively for the first time that the stalk domain is evolving at a rate that is significantly slower than that of the head domain. Additionally, we found that the cross-reactive epitopes in the stalk domain targeted by broadly neutralizing monoclonal antibodies are evolving at an even slower rate compared to the full head and stalk regions of the protein. Finally, a fixed-effects likelihood selection analysis was performed for these virus groups in both the head and stalk domains. While several positive selection sites were found in the head domain, only a single site in the stalk domain of pre-pandemic seasonal H1 hemagglutinin was identified at amino acid position 468 (H1 numbering from methionine). This site is not located in or close to the epitopes of cross-reactive anti-stalk monoclonal antibodies. Furthermore, we found that changes in this site do not significantly impact virus binding or neutralization by human anti-stalk antibodies, suggesting that some positive selection in the stalk domain is independent of immune pressures. We conclude that, while the stalk domain does evolve over time, this evolution is slow and, historically, is not directed to aid in evading neutralizing antibody responses.
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影响因子：
19
作者：
Freidl, G. S.;Meijer, A.;Koopmans, M.
通讯作者：
Koopmans, M.
DOI：
10.1073/pnas.1319058110
发表时间：
2014-01-07
影响因子：
11.1
作者：
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作者：
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影响因子：
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作者：
Gamblin, SJ;Haire, LF;Skehel, JJ
通讯作者：
Skehel, JJ