Trokola A, Dragic T, Arthos J, Binley JM, Olson WC, Allaway GP, Cheng-Mayer C, Robinson J, Maddon PJ, Moore JP; Aaron Diamond AIDS Research Center, New York, NY.
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 HIV-1 is the CD4 molecule, an interaction mediated by the viral surface glycoprotein gp120. How CCR-5 functions during HIV-1 entry has not been defined, but we have shown previously that its beta-chemokine ligands prevent HIV-1-cell fusion. We therefore explored whether CCR-5 serves as a second binding site for HIV-1, subsequent to or simultaneous with the gp120-CD4 interaction. To do this, we used a competition assay based on gp120 inhibition of the binding of the CCR-5 ligand MIP-1beta to its receptor on activated CD4+ T-cells of CCR5+ CD4-cells. We conclude that CD4 binding, while not absolutely necessary for the gp120- CCR-5 interaction, greatly increases its efficiency. Neutralizing Mabs to 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 a major mechanism of virus neutralization.
Keywords: AEGIS, Antigens, CD4, HIV-1, Macrophage Inflammatory Protein-1, Antibodies, Monoclonal, Cell Fusion, Epitopes, Chemokines, CC, Carrier Proteins, Giant Cells, Anti-HIV Agents, AIDS
