CD4-INDUCED CONFORMATIONAL-CHANGES IN THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 GP120 GLYCOPROTEIN - CONSEQUENCES FOR VIRUS ENTRY AND NEUTRALIZATION

Human immunodeficiency virus type 1 (HIV-1) entry into target cells in volves sequential binding of the gp120 exterior envelope glycoprotein to CD4 and to specific chemokine receptors. Soluble CD4 (sCD4) is thou ght to mimic membrane-anchored CD4, and its binding alters the conform ation of the HIV-1 envelope glycoproteins. Two cross-competing monoclo nal antibodies, 17b and CG10, that recognize CD4-inducible gp120 epito pes and that block gp120-chemokine receptor binding were used to inves tigate the nature and functional significance of gp120 conformational changes initiated by CD4 binding. Envelope glycoproteins derived from both T-cell line-adapted and primary HIV-1 isolates exhibited increase d binding of the 17b antibody in the presence of sCD4. CD4-induced exp osure of the 17b epitope on the oligomeric envelope glcoprotein comple x occurred over a wide range of temperatures and involved movement of the gp120 V1/V2 variable loops. Amino acid changes that reduced the ef ficiency of 17b epitope exposure following CD4 binding invariably comp romised the ability of the HIV-1 envelope glycoproteins to form syncyt ia or to support virus entry. Comparison of the CD4 dependence and neu tralization efficiencies of the 17b and CG10 antibodies suggested that the epitopes for these antibodies are minimally accessible following attachment of gp120 to cell surface CD4. These results underscore the functional importance of these CD-l-induced changes in gp120 conformat ion and illustrate viral strategies for sequestering chemokine recepto r-binding regions from the humoral immune response.