Fitness costs limit influenza A virus hemagglutinin glycosylation as an immune evasion strategy
Fitness costs limit influenza A virus hemagglutinin glycosylation as an immune evasion strategy
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DOI：
10.1073/pnas.1108754108
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发表时间：
2011-12-20
影响因子：
11.1
通讯作者：
Yewdell, Jonathan W.
中科院分区：
文献类型：
--
作者：
Das, Suman R.;Hensley, Scott E.;Yewdell, Jonathan W.
在这里，我们解决的问题，为什么甲型流感病毒血凝素（HA）不能逃脱免疫的高糖基化。在对A/波多黎各/8/34特异的几十种单克隆抗体中唯一的是，逃避H28-A2中和需要在球状结构域中的残基131或144处引入N-连接的糖基化的取代。这种逃逸降低了病毒与细胞受体的结合，这必须通过使病毒复制的HA或神经氨酸酶中的额外取代来补偿。循环H1流感病毒的序列分析证实了我们的研究结果在体内的相关性：在残基131处的糖基化的自然发生总是伴随着已知增加HA受体亲合力的补偿突变。在用WT与H28-A2逃逸突变体攻击的接种小鼠中，聚糖介导的抗原性整体降低所赋予的选择性优势被受体亲合力降低的代价所压倒。这些发现表明，虽然N-连接的糖基化可以广泛地降低HA抗原性，但适应性成本限制了其在免疫逃避中的部署。
Here, we address the question of why the influenza A virus hemagglutinin (HA) does not escape immunity by hyperglycosylation. Uniquely among dozens of monoclonal antibodies specific for A/Puerto Rico/8/34, escape from H28-A2 neutralization requires substitutions introducing N-linked glycosylation at residue 131 or 144 in the globular domain. This escape decreases viral binding to cellular receptors, which must be compensated for by additional substitutions in HA or neuraminidase that enable viral replication. Sequence analysis of circulating H1 influenza viruses confirms the in vivo relevance of our findings: natural occurrence of glycosylation at residue 131 is always accompanied by a compensatory mutation known to increase HA receptor avidity. In vaccinated mice challenged with WT vs. H28-A2 escape mutants, the selective advantage conferred by glycan-mediated global reduction in antigenicity is trumped by the costs of diminished receptor avidity. These findings show that, although N-linked glycosylation can broadly diminish HA antigenicity, fitness costs restrict its deployment in immune evasion.