POTENT INHIBITION OF HIV-1 INFECTIVITY IN MACROPHAGES AND LYMPHOCYTESBY A NOVEL CCR5 ANTAGONIST

The chemokine receptors CXCR4 and CCR5 have recently been shown to act as coreceptors, in concert with CD4, for human immunodeficiency virus -type 1 (HIV-1) infection. RANTES and other chemokines that interact w ith CCR5 and block infection of peripheral blood mononuclear cell cult ures inhibit infection of primary macrophages inefficiently at best. I f used to treat HIV-1-infected individuals, these chemokines could fai l to influence HIV replication in nonlymphocyte compartments while pro moting unwanted inflammatory side effects. A derivative of RANTES that was created by chemical modification of the amino terminus, aminooxyp entane (AOP)-RANTES, did not induce chemotaxis and was a subnanomolar antagonist of CCR5 function in monocytes. It potently inhibited infect ion of diverse cell types (including macrophages and lymphocytes) by n onsyncytium-inducing, macrophage-tropic HIV-1 strains. Thus, activatio n of cells by chemokines is not a prerequisite for the inhibition of v iral uptake and replication. Chemokine receptor antagonists like AOP-R ANTES that achieve full receptor occupancy at nanomolar concentrations are strong candidates for the therapy of HIV-1-infected individuals.