CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5.
For efficient entry into target cells, primary macrophage-tropic and laboratory-adapted human immunodeficiency viruses type 1 (HIV-1) require particular chemokine receptors, CCR-5 and CXCR-4, respectively, as well as the primary receptor CD4 (refs 1-6). Here we show that a complex of gp120, the exterior envelope glycoprotein, of macrophage-tropic primary HIV-1 and soluble CD4 interacts specifically with CCR-5 and inhibits the binding of the natural CCR-5 ligands, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta (refs 7, 8). The apparent affinity of the interaction between gp120 and CCR-5 was dramatically lower in the absence of soluble CD4. Additionally, in the absence of gp120, an interaction between a two-domain CD4 fragment and CCR-5 was observed. A gp120 fragment retaining the CD4-binding site and overlapping epitopes was able to interact with CCR-5 only if the V3 loop, which can specify HIV-1 tropism and chemokine receptor choice, was also present on the molecule. Neutralizing antibodies directed against either CD4-induced or V3 epitopes on gp120 blocked the interaction of gp12O-CD4 complexes with CCR-5. These results suggest that HIV-1 attachment to CD4 creates a high-affinity binding site for CCR-5, leading to membrane fusion and virus entry.
LeukoSite, Inc., Cambridge, Massachusetts 02142, USA.
L
L
Wu
N P
NP
Gerard
R
R
Wyatt
H
H
Choe
C
C
Parolin
N
N
Ruffing
A
A
Borsetti
A A
AA
Cardoso
E
E
Desjardin
W
W
Newman
C
C
Gerard
J
J
Sodroski
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001665:Binding Sites; D001667:Binding, Competitive; D015704:CD4 Antigens / Q000378:metabolism*; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D004330:Drosophila; 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; D008561:Membrane Fusion; D051379:Mice; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000378:metabolism; D019713:Receptors, CCR5; D018121:Receptors, Cytokine / Q000378:metabolism*; D015728:Receptors, HIV / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D054405:Chemokine CCL3; 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; C076613:recombinant soluble CD4