Defining Influenza A Virus Hemagglutinin Antigenic Drift by Sequential Monoclonal Antibody Selection
Defining Influenza A Virus Hemagglutinin Antigenic Drift by Sequential Monoclonal Antibody Selection
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DOI：
10.1016/j.chom.2013.02.008
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发表时间：
2013-03-13
影响因子：
30.3
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.
人类甲型流感病毒（IAV）疫苗接种受到“抗原漂移”的限制，这是一种由抗体驱动的快速逃逸，反映了病毒附着蛋白血凝素（HA）球状结构域的氨基酸取代。为了更好地理解漂移，我们使用抗血凝素单克隆抗体（mAbs）顺序选择IAV逃逸突变体。为了消除单克隆或多克隆抗体定义的抗原性，需要12个选择步骤，每个步骤导致血凝素球形结构域的单个氨基酸替换。序列突变体生长稳健，显示出血凝素的结构可塑性，尽管几个血凝素替换需要在神经氨酸酶糖蛋白中进行显性化替换以最大化生长。从具有相同单抗的亲本突变体和序列突变体中选择逃逸突变体揭示了不同的逃逸谱，这归因于抗原性和突变景观的背景变化。由于每个血凝素突变都可能塑造未来的突变空间，因此漂移可能遵循许多随机路径，从而削弱了其不可预测性，并强调了对漂移不敏感疫苗的需求。
Human influenza A virus (IAV) vaccination is limited by "antigenic drift," rapid antibody-driven escape reflecting amino acid substitutions in the globular domain of hemagglutinin (HA), the viral attachment protein. To better understand drift, we used anti-hemagglutinin monoclonal Abs (mAbs) to sequentially select IAV escape mutants. Twelve selection steps, each resulting in a single amino acid substitution in the hemagglutinin globular domain, were required to eliminate antigenicity defined by monoclonal or polyclonal Abs. Sequential mutants grow robustly, showing the structural plasticity of HA, although several hemagglutinin substitutions required an epistatic substitution in the neuraminidase glycoprotein to maximize growth. Selecting escape mutants from parental versus sequential variants with the same mAb revealed distinct escape repertoires, attributed to contextual changes in antigenicity and the mutation landscape. Since each hemagglutinin mutation potentially sculpts future mutation space, drift can follow many stochastic paths, undermining its unpredictability and underscoring the need for drift-insensitive vaccines.