Neutralizing antibodies to human immunodeficiency virus type-1 gp120 induce envelope glycoprotein subunit dissociation.

The spectrum of the anti-human immunodeficiency virus (HIV) neutralizing immune response has been analyzed by the production and characterization of monoclonal antibodies (mAbs) to the viral envelope glycoproteins, gp41 and gp120. Little is known, however, about the neutralization mechanism of these antibodies. Here we show that the binding of a group of neutralizing mAbs that react with regions of the gp120 molecule associated with and including the V2 and V3 loops, the C4 domain and supporting structures, induce the dissociation of gp120 from gp41 on cells infected with the T cell line-adapted HIV-1 molecular clone Hx10. Similar to soluble receptor-induced dissociation of gp120 from gp41, the antibody-induced dissociation is dose- and time-dependent. By contrast, mAbs binding to discontinuous epitopes overlapping the CD4 binding site do not induce gp120 dissociation, implying that mAb induced conformational changes in gp120 are epitope specific, and that HIV neutralization probably involves several mechanisms.

Towards a structure of the HIV-1 envelope glycoprotein gp120: an immunochemical approach

The HIV-1 surface glycoprotein gp120 binds CD4 in the initial state of virus-cell fusion. The extensive glycosylation of gp120 has thus far precluded definition of its structure by crystallographic methods. As an initial approach to a gp120 structure, the surface topology was mapped using antibodies. First, the regions of gp120 that are accessible on the surface of the native molecule, and those that are internal but exposed after denaturation, are identified. Second, epitopes for antibodies that recognize complex surface strutures comprising segments of different domains are identified. Third, we define how mutations in one domain of gp120 influence the binding of antibodies to defined epitopes on other domains. These latter approaches enable us to start to understand the inter-domain interactions that contribute to the overall structure of the gp120 molecule. Information from these studies is being used to model the structures of individual gp120 domains, and the way in which these interact in the folded protein.