AEGiS-08IAC: Synergistic neutralization of HIV-1 by a chimpanzee monoclonal antibody (ChMAb) against a unique epitope near V2 in combination with anti-V3 or anti-CD4 binding site MAbs.

8th International AIDS Conference

Amsterdam, Netherlands — July 19-24, 1992

Synergistic neutralization of HIV-1 by a chimpanzee monoclonal antibody (ChMAb) against a unique epitope near V2 in combination with anti-V3 or anti-CD4 binding site MAbs.

Int Conf AIDS 1992 Jul 19-24; 8:We45 (abstract no. WeA 1003)
Warrier S, Pinter A, Honnen WJ, Chou TC, Tilley SA; Public Health Research Institute, NY, NY.

OBJECTIVE: To develop ChMAbs against new HIV neutralization epitopes and determine the ability of these ChMAbs to synergistically neutralize HIV in combination with mAbs against other neutralization epitopes.

METHODS: A ChMAb was derived by EBV-transformation of PBMC from an HIVIIIB-infected animal that was boosted with recombinant gp160MN. The ChMAb was characterized essentially as described for HuMAb 1125 [Tilley et al. (1991) Res. Virol. 142:247]. Synergistic neutralization experiments were performed using our immunofluorescent focus assay as detailed [Tilley et al. (1992) AIDS Res. Human Retroviruses, in press].

RESULTS: ChMAb C108G has very potent neutralizing activity against IIIB and little, if any, activity against the MN, SF-2, and RF strains. Its activity against IIIB is approximately 25 times that of 0.5 beta, a potent anti-V3 loop mouse mAb, or that of 1125H, a neutralizing HuMAb against the CD4-binding site which we previously described. The C108G epitope is completely dependent on N-linked sugars; these sugars may actually form part of the epitope or may simply be involved in folding gp120 so that the epitope is accessible. Reduction of gp120 disulfides diminishes but does not abolish C108G binding. Binding inhibition studies show that C108G is not inhibited in binding to its epitope by 0.5 beta nor 1125H, but it is partially inhibited by soluble CD4 and by three mouse mAbs recognizing linear or conformational epitopes in or near V2. When combined with 1125H or 0.5 beta at a 1.25 (C108G:1125H or C108G:0.5 beta) ratio, significant synergistic neutralization of HIVIIIB is observed (combination index less than or equal to 0.3 at greater than or equal to 50% neutralization). Synergistic neutralization experiments with the clonal HXB2 strain and C108G paired with other anti-CD4 binding site and anti-V3 loop mAbs are in progress.

CONCLUSIONS: ChMAb C108G identifies a unique carbohydrate-dependent epitope within a newly defined neutralization epitope cluster that is proximal to the V2 region and the CD4 binding site. The very potent neutralization of IIIB strain by C108G and the synergistic neutralization of this strain by C108G paired with either an anti-V3 loop mAb (0.5 beta) or an anti-CD4-binding site HuMAb (1125H) indicates that conserved epitopes in this cluster should be sought and considered as candidates for inclusion in an HIV-1 vaccine. Furthermore, HuMAbs or ChMAbs against such epitopes may be useful in passive immunotherapy against HIV.

Keywords: AEGIS, Antigens, CD4, HIV-1, Epitopes, Antibodies, Monoclonal, Pan troglodytes, Binding Sites, Acquired Immunodeficiency Syndrome, Recombinant Proteins, SK&F 106528, Animal, Human, Mice, ICA8
920719
WeA1003