title: Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist.
abstract: 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.
authors.affiliation: Virology Group, Chester Beatty Laboratories, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: G
authors.initials: G
authors.lastname: Simmons
authors.forename: P R
authors.initials: PR
authors.lastname: Clapham
authors.forename: L
authors.initials: L
authors.lastname: Picard
authors.forename: R E
authors.initials: RE
authors.lastname: Offord
authors.forename: M M
authors.initials: MM
authors.lastname: Rosenkilde
authors.forename: T W
authors.initials: TW
authors.lastname: Schwartz
authors.forename: R
authors.initials: R
authors.lastname: Buser
authors.forename: T N
authors.initials: TN
authors.lastname: Wells
authors.forename: A E
authors.initials: AE
authors.lastname: Proudfoot
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D015704:CD4 Antigens / Q000378:metabolism; D002415:Cats; D002460:Cell Line; D002478:Cells, Cultured; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000821:virology*; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015728:Receptors, HIV / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D015704:CD4 Antigens; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D015728:Receptors, HIV