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Structural basis for norovirus neutralization by an HBGA blocking human IgA antibody

Significance Attachment to cellular glycans is a critical process in cell entry for several viruses. Antibodies that block this essential step can serve as neutralizing antibodies. Among human noroviruses (NoVs), serum antibodies that block histo-blood group antigen (HBGA) binding serve as correlates of protection. Escape from neutralization with evolving human NoVs (HuNoVs) through antigenic variation and differential HBGA binding is suggested to form a basis for the emergence of new strains. Currently, we are aware of no structural insights into antibody-mediated HBGA blockade or neutralization, or how emerging strains escape such neutralization. Our study reveals how a human IgA monoclonal antibody binds and blocks HBGA binding and indicates how other strains escape host immunity, laying the structural framework for understanding the immune correlates of protection against HuNoVs. Human noroviruses (HuNoVs) cause sporadic and epidemic gastroenteritis worldwide. They are classified into two major genogroups (GI and GII), with each genogroup further divided into multiple genotypes. Susceptibility to these viruses is influenced by genetically determined histo-blood group antigen (HBGA) expression. HBGAs function as cell attachment factors by binding to a surface-exposed region in the protruding (P) domain of the capsid protein. Sequence variations in this region that result in differential HBGA binding patterns and antigenicity are suggested to form a basis for strain diversification. Recent studies show that serum antibodies that block HBGA binding correlate with protection against illness. Although genogroup-dependent variation in HBGA binding specificity is structurally well characterized, an understanding of how antibodies block HBGA binding and how genotypic variations affect such blockade is lacking. Our crystallographic studies of the GI.1 P domain in complex with the Fab fragment of a human IgA monoclonal antibody (IgA 5I2) with HBGA blocking activity show that the antibody recognizes a conformational epitope formed by two surface-exposed loop clusters in the P domain. The antibody engulfs the HBGA binding site but does not affect its structural integrity. An unusual feature of the antigen recognition by IgA 5I2 is the predominant involvement of the CDR light chain 1 in contrast to the commonly observed CDR heavy chain 3, providing a unique perspective into antibody diversity in antigen recognition. Identification of the antigenic site in the P domain shows how genotypic variations might allow escape from antibody neutralization and exemplifies the interplay between antigenicity and HBGA specificity in HuNoV evolution.