Maurer Daniel P, Vu Mya, Schmidt Aaron G
Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA 02139, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA 02139, USA.
Immunity. 2025 Mar 11;58(3):716-727.e6. doi: 10.1016/j.immuni.2025.02.006. Epub 2025 Feb 28.
Initial exposure to a rapidly evolving virus establishes B cell memory that biases later responses to antigenically drifted strains. This "immune imprinting" implies that subsequent exposure to a drifted strain can induce affinity maturation of memory B cells toward cross-reactivity with the drifted strain and hence toward greater overall breadth. Here, we used deep mutational scanning of H1 influenza hemagglutinins (HAs) to investigate how viruses evolve in response to these broad antibody response. We identified escape mutations from clonal antibody lineages that targeted the receptor binding site and lateral patch. By adjusting the antigen-antibody contacts, antibody affinity maturation restricted the potential escape routes for the eliciting strain. However, escape occurred readily in drifted strains. We attribute this escape-prone property of the drifted strains to epistatic networks within HA. Our data explain how the influenza virus continues to evolve in the human population by escaping even broad antibody responses.
初次接触快速演变的病毒会建立B细胞记忆，这种记忆会使后续对抗原性发生漂移的毒株的反应产生偏差。这种“免疫印记”意味着，随后接触发生漂移的毒株可诱导记忆B细胞的亲和力成熟，使其与发生漂移的毒株产生交叉反应，从而具有更广泛的总体广度。在此，我们利用对H1流感血凝素（HA）进行深度突变扫描，来研究病毒如何针对这些广泛的抗体反应进行进化。我们确定了来自靶向受体结合位点和外侧区的克隆抗体谱系的逃逸突变。通过调整抗原-抗体接触，抗体亲和力成熟限制了引发毒株的潜在逃逸途径。然而，在发生漂移的毒株中逃逸很容易发生。我们将发生漂移的毒株这种易于逃逸的特性归因于HA内的上位网络。我们的数据解释了流感病毒如何通过逃避甚至广泛的抗体反应在人群中持续进化。
