What Antibody Repertoires See: Structural and Immunogenetic Insights Into Influenza A Virus Hemagglutinin Recognition
TL;DR
Together, these examples show that what antibody repertoires “see” is determined by the interplay between viral glycoprotein structure, B cell precursor availability, somatic evolution, and population‐level immunoglobulin diversity.
Abstract
Human infection with or vaccination against influenza A virus has been one of the most informative systems for understanding how human antibody repertoires recognize viral glycoproteins. Decades of antibody isolation, repertoire sequencing, lineage tracing, serology, viral antigenic evolution, and structural biology have shown that antibody recognition is not simply a matter of “which epitope is targeted.” Instead, each surface on the viral hemagglutinin (HA) presents a distinct structural problem for the immune system. Repeated exposures through infection and vaccination coupled with continuous antigenic drift generate complex immune histories and reveal which viral surfaces evolve under antibody pressure. Structural studies have transformed the field by showing how antibody repertoires solve epitope‐specific recognition problems. Some epitopes, such as the HA central stem, recruit highly stereotyped genetic and structural solutions. Others, such as the receptor‐binding site, can be approached by genetically diverse antibodies that converge on common structural solutions of receptor mimicry. Additional epitopes, including the lateral patch, anchor, head interface, and head‐stem junction, reveal intermediate patterns of repertoire constraint. Together, these examples show that what antibody repertoires “see” is determined by the interplay between viral glycoprotein structure, B cell precursor availability, somatic evolution, and population‐level immunoglobulin diversity.