CD4-dependent, antibody-sensitive interactions between HIV-1 and its co-receptor CCR-5.
The beta-chemokine receptor CCR-5 is an essential co-factor for fusion of HIV-1 strains of the non-syncytium-inducing (NSI) phenotype with CD4+ T-cells. The primary binding site for human immunodeficiency virus (HIV)-1 is the CD4 molecule, and the interaction is mediated by the viral surface glycoprotein gp120 (refs 6, 7). The mechanism of CCR-5 function during HIV-1 entry has not been defined, but we have shown previously that its beta-chemokine ligands prevent HIV-1 from fusing with the cell. We therefore investigated whether CCR-5 acts as a second binding site for HIV-1 simultaneously with or subsequent to the interaction between gp120 and CD4. We used a competition assay based on gp120 inhibition of the binding of the CCR-5 ligand, macrophage inflammatory protein (MIP)-1beta, to its receptor on activated CD4+ T cells or CCR-5-positive CD4- cells. We conclude that CD4 binding, although not absolutely necessary for the gp120-CCR-5 interaction, greatly increases its efficiency. Neutralizing monoclonal antibodies against several sites on gp120, including the V3 loop and CD4-induced epitopes, inhibited the interaction of gp120 with CCR-5, without affecting gp120-CD4 binding. Interference with HIV-1 binding to one or both of its receptors (CD4 and CCR-5) may be an important mechanism of virus neutralization.
Trkola
A
A
The Aaron Diamond AIDS Research Centre, The Rockefeller University, New York 10016, USA.
Dragic
T
T
Arthos
J
J
Binley
J M
JM
Olson
W C
WC
Allaway
G P
GP
Cheng-Mayer
C
C
Robinson
J
J
Maddon
P J
PJ
Moore
J P
JP
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D001667:Binding, Competitive; D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D054407:Chemokine CCL4; D015483:HIV Antibodies / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011487:Protein Conformation; D019713:Receptors, CCR5; D018121:Receptors, Cytokine / Q000378:metabolism*; D015728:Receptors, HIV / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D054407:Chemokine CCL4; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D019402:Macrophage Inflammatory Proteins; D010446:Peptide Fragments; D019713:Receptors, CCR5; D018121:Receptors, Cytokine; D015728:Receptors, HIV; D011994:Recombinant Proteins