Wu L, Gerard NP, Wyatt R, Choe H, Parolin C, Ruffing N, Borsetti A, Cardoso AA, Desjardin E, Newman W, Gerard C, Sodroski J; LeukoSite, Inc., Cambridge, MA.
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. 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 MIP1beta. 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(2,9-11), was also present on the molecule. Neutralizing antibodies directed against either CD4-induced or V3 epitopes on gp120 blocked the interaction of gp120-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.
Keywords: AEGIS, Antigens, CD4, HIV-1, Carrier Proteins, Membrane Fusion, Epitopes, Recombinant Proteins, host factors, Binding Sites, SK&F 106528, Human, virology, AIDS
