title: Functional maturation of the human antibody response to rotavirus.
abstract: Infant Abs induced by viruses exhibit poor functional activity compared with those of adults. The human B cell response to rotavirus is dominated by use of the V(H)1-46 gene segment in both adults and infants, but only adult sequences are highly mutated. We investigated in detail the kinetic, structural, and functional advantage conferred by individual naturally occurring somatic mutations in rotavirus-specific human Abs encoded by the immunodominant V(H)1-46 gene segment. Adult Abs achieved enhanced binding through naturally occurring somatic mutations in the H chain CDR2 region that conferred a markedly prolonged off-rate and a desirable increase in antiviral potency. Three-dimensional cryoelectron microscopy studies of Ag-Ab complexes revealed the mechanism of viral inhibition to be the binding of high-affinity Abs at the viral RNA release pore in the double-layer particle. These structure-function studies suggest a molecular basis for the poor quality of Abs made in infancy following virus infection or immunization.
authors.affiliation: Departments of Microbiology and Immunology, Vanderbilt University, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Kallewaard
authors.forename: Brett A
authors.initials: BA
authors.lastname: McKinney
authors.forename: Yingqi
authors.initials: Y
authors.lastname: Gu
authors.forename: Annie
authors.initials: A
authors.lastname: Chen
authors.forename: B V Venkataram
authors.initials: BV
authors.lastname: Prasad
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
mesh_terms: D000914:Antibodies, Viral / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D000956:Antigens, Viral / Q000276:immunology / Q000378:metabolism; D001666:Binding Sites, Antibody / Q000235:genetics; D036022:Capsid Proteins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000378:metabolism; D007072:Immunoglobulin D / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology / Q000648:ultrastructure; D007140:Immunoglobulin Fab Fragments / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics / Q000648:ultrastructure; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics / Q000648:ultrastructure; D007700:Kinetics; D012136:Respiratory Syncytial Viruses / Q000235:genetics / Q000276:immunology; D012401:Rotavirus / Q000235:genetics / Q000276:immunology*; D027041:Somatic Hypermutation, Immunoglobulin
chemical_list: D000914:Antibodies, Viral; D000956:Antigens, Viral; D036022:Capsid Proteins; D016056:Immunodominant Epitopes; D007072:Immunoglobulin D; D007140:Immunoglobulin Fab Fragments; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; C061332:VP6 protein, Rotavirus