CD4-INDUCED INTERACTION OF PRIMARY HIV-1 GP120 GLYCOPROTEINS WITH THECHEMOKINE RECEPTOR CCR-5

FOR efficient entry into target cells, primary macrophage-tropic and l aboratory-adapted human immunodeficiency viruses type 1 (HIV-1) requir e particular chemokine receptors, CCR-5 and CXCR-4, respectively, as w ell as the primary receptor CD4 (refs 1-6). Here we show that a comple x of gp120, the exterior envelope glycoprotein, of macrophage-tropic p rimary HIV-1 and soluble CD4 interacts specifically with CCR-5 and inh ibits the binding of the natural CCR-5 ligands, macrophage inflammator y protein (MIP)-1 alpha and MLP-1 beta (refs 7, 8). The apparent affin ity 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 observe d. A gp120 fragment retaining the CD4-binding site and overlapping epi topes was able to interact with CCR-5 only if the V3 loop, which can s pecify HIV-1 tropism and chemokine receptor choice(2,9-11), was also p resent on the molecule. Neutralizing antibodies directed against eithe r 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 mem brane fusion and virus entry.