Conformational changes induced in the human immunodeficiency virus envelope glycoprotein by soluble CD4 binding.
The human immunodeficiency virus (HIV) binds to the surface of T lymphocytes and other cells of the immune system via a high affinity interaction between CD4 and the HIV outer envelope glycoprotein, gp120. By analogy with certain other enveloped viruses, receptor binding by HIV may be followed by exposure of the hydrophobic NH2 terminus of its transmembrane glycoprotein, gp41, and fusion of the virus and cell membranes. A similar sequence of events is thought to take place between HIV-infected and uninfected CD4+ cells, resulting in their fusion to form syncytia. In this study, we have used a soluble, recombinant form of CD4 (sCD4) to model events taking place after receptor binding by the HIV envelope glycoproteins. We demonstrate that the complexing of sCD4 with gp120 induces conformational changes within envelope glycoprotein oligomers. This was measured on HIV-1-infected cells by the increased binding of antibodies to the gp120/V3 loops, and on the surface of virions by increased cleavage of this loop by an exogenous proteinase. At 37 degrees C, these conformational changes are coordinate with the dissociation of gp120/sCD4 complexes from gp41, and the increased exposure of gp41 epitopes. At 4 degrees C, gp120 dissociation from the cell surface does not occur, but increased exposure of both gp120/V3 and gp41 epitopes is detected. We propose that these events occurring after CD4 binding are integral components of the membrane fusion reaction between HIV or HIV-infected cells and CD4+ cells.
Sattentau
Q J
QJ
Academic Department of Genito-Urinary Medicine, University College and Middlesex School of Medicine, London, United Kingdom.
Moore
J P
JP
D000911:Antibodies, Monoclonal / Q000378:metabolism; D015153:Blotting, Western; D015704:CD4 Antigens / Q000378:metabolism*; D000939:Epitopes / Q000276:immunology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015483:HIV Antibodies / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism*; D015700:HIV Envelope Protein gp41 / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D011487:Protein Conformation; D015728:Receptors, HIV; D011994:Recombinant Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000382:microbiology; D014771:Virion
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D015728:Receptors, HIV; D011994:Recombinant Proteins