CHARACTERIZATION OF THE VARIABLE REGIONS OF A CHIMPANZEE MONOCLONAL-ANTIBODY WITH POTENT NEUTRALIZING ACTIVITY AGAINST HIV-1

The variable (V) regions of C108G, a potent neutralizing chimpanzee mA b against a glycan-dependent epitope in the V2 region of HIV-I gp120, have been characterized for reactivity with human V-H and V-kappa fami ly-specific antisera, and their nucleotide sequences have been determi ned and analysed. To our knowledge, this is the first study characteri zing expressed chimpanzee V-H and V-kappa genes. Results show that C10 8G expresses members of the V(H)3 and V(kappa)1 families, the largest V-H and V-kappa families in humans, respectively. Nucleotide and amino acid sequence analyses reveal that C108G V-H is most homologous to th e human V(H)3 germline gene, hsigdp33 or V3-43, and the human J(H)4 mi nigene. The human germline V(kappa)1 gene that is most homologous to C 108G V-kappa, hsigk1012, was previously observed in unmutated form in a human autoantibody with anti-i red blood cell antigen specificity an d in seven human Fabs and a mAb directed against epitopes overlapping the CD4-binding site of HIV-I gp 120. This germline gene was unmutated in three of the human Fabs and was somatically mutated in the other f our Fabs and the mAb. In addition, the J(kappa) minigene used in C108G V-kappa, J(kappa)2, is apparently over-represented in anti-HIV-1 mAbs /Fabs; this minigene was used in 61% of the anti-gp 120 human Fabs rec ently described and in three other anti-CD4-binding site human mAbs de rived by EBV transformation. While the significance of these findings is unclear, they may suggest a bias in V-kappa/J(kappa) gene usage and /or network regulation involving an hsigk1012/J(kappa)2 idiotope(s) in the antibody response to HIV-1. Both the C108G V-H and V-kappa genes showed evidence of somatic mutation and antigen selection that apparen tly occurred in vivo during chronic exposure to HIV-1 and its antigens . Surprisingly, this somatic mutation was most profound in the CDR3 re gion of C108G V-kappa; this region shared only 48% nucleotide homology with hsigk1012 contrasted with a homology of 94% over the remainder o f these two V gene sequences. Perhaps the most significant finding of this study is that the expressed V-H and V-kappa genes of chimpanzee m Ab C108G are no more divergent from their most homologous human germli ne genes than are the expressed V genes of several recently characteri zed human anti-HIV-l mAbs/Fabs from their apparent human germline gene s. This suggests that chimpanzee mAbs are no more likely to elicit del eterious anti-immunoglobulin responses in humans than are human mAbs a nd emphasizes the potential for development of chimpanzee mAbs as immu notherapeutic agents.