Characterization of the variable regions of a chimpanzee monoclonal antibody with potent neutralizing activity against HIV-1

Abstract

The variable (V) regions of C108G, a potent neutralizing chimpanzee mAb against a glycan-dependent epitope in the V2 region of HIV-1 gp120, have been characterized for reactivity with human V H and V κ family-specific antisera, and their nucleotide sequences have been determined and analysed. To our knowledge, this is the first study characterizing expressed chimpanzee V H and V κ genes. Results show that C108G expresses members of the V H3 and V κ1 families, the largest V H and V κ families in humans, respectively. Nucleotide and amino acid sequence analyses reveal that C108G V H is most homologous to the human V H3 germline gene, hsigdp33 or V3-43, and the human J H4 minigene. The human germline V κ1 gene that is most homologous to C108G V κ, hsigk1012, was previously observed in unmutated form in a human autoantibody with anti-i red blood cell antigen specificity and in seven human Fabs and a mAb directed against epitopes overlapping the CD4-binding site of HIV-1 gp120. This germline gene was unmutated in three of the human Fabs and was somatically mutated in the other four Fabs and the mAb. In addition, the J κ minigene used in C108G V κ, J κ2, is apparently over-represented in anti-HIV-1 mAbs Fabs ; this minigene was used in 61% of the anti-gp120 human Fabs recently described and in three other anti-CD4-binding site human mAbs derived by EBV transformation. While the significance of these findings is unclear, they may suggest a bias in V κ J κ gene usage and/or network regulation involving an hsigk1012 J κ2 idiotope(s) in the antibody response to HIV-1. Both the C108G V H and V κ genes showed evidence of somatic mutation and antigen selection that apparently occurred in vivo during chronic exposure to HIV-1 and its antigens. Surprisingly, this somatic mutation was most profound in the CDR3 region of C108G V κ; this region shared only 48% nucleotide homology with hsigk1012 contrasted with a homology of 94% over the remainder of these two V gene sequences. Perhaps the most significant finding of this study is that the expressed V H and V κ genes of chimpanzee mAb C108G are no more divergent from their most homologous human germline genes than are the expressed V genes of several recently characterized human anti-HIV-1 mAbs Fabs from their apparent human germline genes. This suggests that chimpanzee mAbs are no more likely to elicit deleterious anti-immunoglobulin responses in humans than are human mAbs and emphasizes the potential for development of chimpanzee mAbs as immunotherapeutic agents.