Non-germ-line encoded residues are critical for effective antibody recognition of a poorly immunogenic neutralization epitope on glycoprotein B of human cytomegalovirus.
The capability of the antibody (Ab) repertoire to mount a response to appropriate epitopes on infectious agents will strongly affect the ability of the immune system to provide protection against disease. Certain epitopes may be poor inducers of immunity but are nevertheless able to promote biologically important protection when recognized by the immune repertoire. We have investigated the recognition by Ab of one such poorly immunogenic target, antigenic domain 2 (AD-2) on human cytomegalovirus glycoprotein B. To date, only two well-characterized human monoclonal Ab reactive with this epitope are known. To define parameters important for establishment of a human paratope recognizing this epitope, we created variants of the variable genes utilized by one of these Ab and used phage display technology to select Ab fragments with retained antigen specificity. We show here that residues in the first complementarity determining region of both the heavy and the light chain are involved in determining the AD-2 specificity and, in addition, that key mutations in the germ-line sequence are required for effective interaction with this epitope. Thus, the products of the human germ-line IGHV3-30 and IGKV3-11 genes, the only V genes that have been demonstrated to participate in an AD-2 specific Ab response, do not have the intrinsic features required for high-affinity recognition of this epitope. We propose that the inability of the human germ-line gene-encoded Ab repertoire to directly recognize this and possibly other antigenic determinants results in their poor immunogenicity in vivo. This may favor responses to other epitopes, which have a high-affinity imprint in the human germ-line Ab repertoire.
Lantto
Johan
J
Department of Immunotechnology, Lund University, Lund, Sweden.
Lindroth
Ylva
Y
Ohlin
Mats
M
D000595:Amino Acid Sequence; D000914:Antibodies, Viral / Q000737:chemistry* / Q000276:immunology; D000915:Antibody Affinity; D001483:Base Sequence; D022801:Complementarity Determining Regions; D003587:Cytomegalovirus / Q000276:immunology*; D000939:Epitopes; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry; D007135:Immunoglobulin Variable Region / Q000737:chemistry; D008969:Molecular Sequence Data; D014759:Viral Envelope Proteins / Q000276:immunology*
D000914:Antibodies, Viral; D022801:Complementarity Determining Regions; D000939:Epitopes; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus