Functional maturation of the human antibody response to rotavirus.

Kallewaard NL, McKinney BA, Gu Y, Chen A, Prasad BV, Crowe JE
J Immunol. 2008 180 (6): 3980-9

PMID: 18322207 · DOI:10.4049/jimmunol.180.6.3980

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.

MeSH Terms (14)

Antibodies, Viral Antigens, Viral Binding Sites, Antibody Capsid Proteins Humans Immunodominant Epitopes Immunoglobulin D Immunoglobulin Fab Fragments Immunoglobulin Heavy Chains Immunoglobulin Variable Region Kinetics Respiratory Syncytial Viruses Rotavirus Somatic Hypermutation, Immunoglobulin

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