HIV-1 infection through the CCR5 receptor is blocked by receptor dimerization

The identification of the chemokine receptors as receptors for HIV-1 has bo osted interest in these molecules, raising expectations for the development of new strategies to prevent HIV-1 infection. The discovery that chemokine s block HIV-1 replication has focused attention on identifying their mechan ism of action. Previous studies concluded that this inhibitory effect may b e mediated by steric hindrance or by receptor down-regulation. We have iden tified a CCR5 receptor-specific mAb that neither competes with the chemokin e for binding nor triggers signaling, as measured by Ca2+ influx or chemota xis. The antibody neither triggers receptor down-regulation nor interferes with the R5 JRFL viral strain gp120 binding to CCR5, but blocks HIV-1 repli cation in both in vitro assays using peripheral blood mononuclear cells as HIV-1 targets, as well as in vivo using human peripheral blood mononuclear cell-reconstituted SCID (severe combined immunodeficient) mice. Our evidenc e shows that the anti-CCR5 mAb efficiently prevents HIV-1 infection by indu cing receptor dimerization. Chemokine receptor dimerization also is induced by chemokines and is required for their anti-HIV-1 activity. In addition t o providing a molecular mechanism through which chemokines black HIV-1 infe ction, these results illustrate the prospects for developing new tools that possess HIV-1 suppressor activity, but lack the undesired inflammatory sid e effects of the chemokines.