Germline V-genes sculpt the binding site of a family of antibodies neutralizing human cytomegalovirus

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Abstract
Immunoglobulin genes are generated somatically through specialized mechanisms resulting in a vast repertoire of antigen‐binding sites. Despite the stochastic nature of these processes, the V‐genes that encode most of the antigen‐combining site are under positive evolutionary selection, raising the possibility that V‐genes have been selected to encode key structural features of binding sites of protective antibodies against certain pathogens. Human, neutralizing antibodies to human cytomegalovirus that bind the AD‐2S1 epitope on its gB envelope protein repeatedly use a pair of well‐conserved, germline V‐genes IGHV3‐30 and IGKV3‐11 . Here, we present crystallographic, kinetic and thermodynamic analyses of the binding site of such an antibody and that of its primary immunoglobulin ancestor. These show that these germline V‐genes encode key side chain contacts with the viral antigen and thereby dictate key structural features of the hypermutated, high‐affinity neutralizing antibody. V‐genes may thus encode an innate, protective immunological memory that targets vulnerable, invariant sites on multiple pathogens.