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Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist.
Simmons G; Clapham PR; Picard L; Offord RE; Rosenkilde MM; Schwartz TW;
July 30, 1997
Science. 1997 Apr 11;276(5310):276-9. Unique Identifier : AIDSLINE

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 with CCR5 and block infection of peripheral blood mononuclear cell cultures inhibit infection of primary macrophages inefficiently at best. If used to treat HIV-1-infected individuals, these chemokines could fail to influence HIV replication in nonlymphocyte compartments while promoting unwanted inflammatory side effects. A derivative of RANTES that was created by chemical modification of the amino terminus, aminooxypentane (AOP)-RANTES, did not induce chemotaxis and was a subnanomolar antagonist of CCR5 function in monocytes. It potently inhibited infection of diverse cell types (including macrophages and lymphocytes) by nonsyncytium-inducing, macrophage-tropic HIV-1 strains. Thus, activation of cells by chemokines is not a prerequisite for the inhibition of viral uptake and replication. Chemokine receptor antagonists like AOP-RANTES that achieve full receptor occupancy at nanomolar concentrations are strong candidates for the therapy of HIV-1-infected individuals.

*HIV-1/DRUG EFFECTS *Macrophages/VIROLOGY *Receptors, Cytokine/ANTAGONISTS & INHIB *Receptors, HIV/ANTAGONISTS & INHIB *T-Lymphocytes/VIROLOGY