He Yuanyuan, Guo Zijian, Vahey Michael D
Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri, USA.
Center for Biomolecular Condensates, Washington University in St. Louis, St. Louis, Missouri, USA.
bioRxiv. 2024 Nov 21:2024.11.18.624200. doi: 10.1101/2024.11.18.624200.
During repeated virus exposure, pre-existing antibodies can mask viral epitopes by competing with B cell receptors for antigen. Although this phenomenon has the potential to steer B cell responses away from conserved epitopes, the factors that influence epitope masking by competing antibodies remain unclear. Using engineered, influenza-reactive B cells, we investigate how antibodies influence the accessibility of epitopes on the viral surface. We find that membrane-proximal epitopes on influenza hemagglutinin are fundamentally at a disadvantage for B cell recognition because they can be blocked by both directly and indirectly competing antibodies. While many influenza-specific antibodies can inhibit B cell activation, the potency of masking depends on proximity of the targeted epitopes as well as antibody affinity, kinetics, and valency. Although most antibodies are inhibitory, we identify one that can enhance accessibility of hidden viral epitopes. Together, these findings establish rules for epitope masking that could help advance immunogen design.
在反复接触病毒的过程中，预先存在的抗体可通过与B细胞受体竞争抗原，从而掩盖病毒表位。尽管这种现象有可能使B细胞反应避开保守表位，但影响竞争性抗体对表位掩盖作用的因素仍不清楚。利用经过改造的、对流感病毒有反应的B细胞，我们研究了抗体如何影响病毒表面表位的可及性。我们发现，流感血凝素上靠近膜的表位在B细胞识别方面从根本上处于劣势，因为它们可被直接和间接竞争的抗体阻断。虽然许多流感特异性抗体可抑制B细胞活化，但掩盖作用的效力取决于靶向表位的接近程度以及抗体的亲和力、动力学和价态。尽管大多数抗体具有抑制作用，但我们鉴定出一种可增强隐藏病毒表位可及性的抗体。这些发现共同确立了表位掩盖的规则，有助于推进免疫原设计。
