NEUTRALIZING RESPONSES TO HIV GP120 COMPLEXED WITH CD4 A

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We propose to investigate the influence of specific ligands on the antigen processing and presentation as well as on the fine specificities of the resulting antibody response to the HIV envelope proteins and the cellular receptors for the virus. The final goal of this study is to modulate the response in order to obtain higher proportions of antibodies capable of neutralizing the virus and/or blocking at any stage and by any mechanism the process of membrane fusion which allows the virus to penetrate the target cell. According to our previous studies in a non related system, monoclonal antibodies directed to critical sites of the antigen are choice macromolecular ligands for influencing uptake, processing and presentation to T cells. We shall immunize animals (mice, rabbits) with HIV gp120 envelope protein complexed with different monoclonal antibodies directed at known epitopes, and determine the fine specificity and functional characteristics of the resulting cellular and antibody responses. In parallel, taking advantage of the fact that the binding between gp120 and recombinant CD4 in soluble form has the specificity and the affinity of a strong immune interaction (Ko = 10-9n), we are presently determining the quantitative and the qualitative effects of triggering the immune response by the injection of complexed versus free CD4 and gp120. Our current results in this system show an exceptionally high syncitia-blocking titer in mice and rabbits injected with CD4-gp120. The blocking antibody appears to be directed to the CD4 moiety, and to act after the first contact of the viral envelope with the cell receptor has taken place. We shall analyze this novel mechanism of HIV neutralization by means of monoclonal antibodies obtained from the mice immunized with CD4-gp120 complex and test the hypotheses a) that a number of conformational transitions take place in gp160 as well as in CD4, uncovering or generating structures susceptible to neutralizing antibodies, and b) that such neoantigens localized in the receptor can be immunogenic even when the native CD4 is "self" molecule, e.g. in primates and man.