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ABSTRACT: The potential utility of gp120 complexed to CD4 in HIV-1 vaccine development has been shown by studies in which such complexes were able to induce antibodies to cryptic gp120 epitopes and to generate broadly neutralizing humoral responses. Recently, a full-length single-chain (FLSC) analogue of the gp120–CD4 receptor complex, consisting of HIV-1 Bal gp120 joined to the D1D2 domains of CD4 by a 20-amino-acid linker, has been described. We tested the immunogenicity of this protein in transgenic XMG2 XenoMouse® mice that express human IgG2 with κ light chain loci and that model human humoral immune responses. Six mice immunized with purified FLSC all developed high antibody titers for the immunogen, but none of the sera possessed neutralizing activities against HIVBaL or HIVSF162 virus. A panel of 39 human monoclonal antibodies (mAbs) were generated from an immunized mouse. Only three of these mAbs recognized linear epitopes. One of these mapped to the V3 region and two to the C-terminus of gp120. The majority of the mAbs (36/39) were directed against one of two distinct conformational epitopes specific for FLSC. Binding of representative mAbs to these epitopes was not blocked by antibodies to a number of known targets on gp120, but was enhanced by binding of 17b, directed to a CD4-induced epitope on gp120. None of the FLSC-induced mAbs possessed neutralization activity against either HIV-1 BaL or SF162. These results suggest that a major portion of the antibody response against the FLSC protein may be directed against immunodominant conformational epitopes unique to the fusion protein that do not mediate viral neutralization. This property may limit the utility of this chimeric molecule as an HIV-1 vaccine candidate.