Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
J Virol. 2018 Sep 12;92(19). doi: 10.1128/JVI.00859-18. Print 2018 Oct 1.
Influenza viruses use distinct antibody escape mechanisms depending on the overall complexity of the antibody response that is encountered. When grown in the presence of a hemagglutinin (HA) monoclonal antibody, influenza viruses typically acquire a single HA mutation that reduces the binding of that specific monoclonal antibody. In contrast, when confronted with mixtures of HA monoclonal antibodies or polyclonal sera that have antibodies that bind several HA epitopes, influenza viruses acquire mutations that increase HA binding to host cells. Recent data from our laboratory and others suggest that some humans possess antibodies that are narrowly focused on HA epitopes that were present in influenza virus strains that they were likely exposed to in childhood. Here, we completed a series of experiments to determine if humans with narrowly focused HA antibody responses are able to select for influenza virus antigenic escape variants We identified three human donors that possessed HA antibody responses that were heavily focused on a single HA antigenic site. Sera from all three of these donors selected single HA escape mutations during passage experiments, similar to what has been previously reported for single monoclonal antibodies. These single HA mutations directly reduced binding of serum antibodies used for selection. We propose that new antigenic variants of influenza viruses might originate in individuals who produce antibodies that are narrowly focused on HA epitopes that were present in viral strains that they encountered in childhood. Influenza vaccine strains must be updated frequently since circulating viral strains continuously change in antigenically important epitopes. Our previous studies have demonstrated that some individuals possess antibody responses that are narrowly focused on epitopes that were present in viral strains that they encountered during childhood. Here, we show that influenza viruses rapidly escape this type of polyclonal antibody response when grown by acquiring single mutations that directly prevent antibody binding. These studies improve our understanding of how influenza viruses evolve when confronted with narrowly focused polyclonal human antibodies.
流感病毒根据所遇到的抗体反应的整体复杂性，使用不同的抗体逃逸机制。当在血凝素 (HA) 单克隆抗体存在的情况下生长时，流感病毒通常会获得单一的 HA 突变，从而降低该特定单克隆抗体的结合能力。相比之下，当面对包含多个 HA 表位的 HA 单克隆抗体或多克隆血清混合物时，流感病毒会获得增加 HA 与宿主细胞结合的突变。我们实验室和其他实验室的最近数据表明，一些人拥有针对其在儿童时期可能接触过的流感病毒株中存在的 HA 表位的狭窄焦点的抗体。在这里，我们完成了一系列实验，以确定具有狭窄焦点 HA 抗体反应的人是否能够选择流感病毒抗原逃逸变体。我们确定了三个具有高度集中于单个 HA 抗原位点的 HA 抗体反应的人类供体。来自这三个供体的血清在传代实验中都选择了单个 HA 逃逸突变，类似于先前报道的单个单克隆抗体。这些单一的 HA 突变直接降低了用于选择的血清抗体的结合。我们提出，流感病毒的新抗原变体可能起源于产生针对其在儿童时期遇到的病毒株中存在的 HA 表位的狭窄焦点的抗体的个体。由于循环病毒株在抗原性重要表位上不断变化，因此需要经常更新流感疫苗株。我们之前的研究表明，一些个体拥有针对其在儿童时期遇到的病毒株中存在的表位的狭窄焦点的抗体反应。在这里，我们表明，当通过获得直接阻止抗体结合的单一突变来生长时，流感病毒会迅速逃避这种类型的多克隆抗体反应。这些研究提高了我们对流感病毒在面对狭窄焦点的多克隆人抗体时如何进化的理解。
