Potent Inhibition of HIV-1 Infectivity in Macrophages and Lymphocytes by a Novel CCR5 Antagonist

• Published in: Science (American Association for the Advancement of Science) Vol. 276; no. 5310; pp. 276 - 279
• Main Authors: Simmons, Graham, Clapham, Paul R., Picard, Laurent, Offord, Robin E., Rosenkilde, Mette M., Schwartz, Thue W., Buser, Raphaële, Timothy N. C. Wells, Amanda E. I. Proudfoot
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for the Advancement of Science 11.04.1997; American Association for the Advancement of Science; The American Association for the Advancement of Science
• Subjects: AIDS/HIV; Animals; Binding, Competitive; Biological and medical sciences; Cats; CD4 Antigens - metabolism; Cell Line; Cells, Cultured; Cellular biology; Chemokine CCL4; Chemokine CCL5 - metabolism; Chemokine CCL5 - pharmacology; Chemokines; Chemotaxis, Leukocyte; Cultured cells; Fundamental and applied biological sciences. Psychology; HEK293 cells; HeLa Cells; HIV; HIV 1; HIV infection; HIV infections; HIV-1 - drug effects; HIV-1 - physiology; Human immunodeficiency virus; human immunodeficiency virus 1; Humans; Infections; Inhibition; Macrophage Inflammatory Proteins - metabolism; Macrophages; Macrophages - drug effects; Macrophages - virology; Medical research; Microbiology; Monocytes; Receptors; Receptors, CCR5; Receptors, Chemokine; Receptors, Cytokine - antagonists & inhibitors; Receptors, Cytokine - metabolism; Receptors, HIV - antagonists & inhibitors; Receptors, HIV - metabolism; Replicative cycle, interference, host-virus relations, pathogenicity, miscellaneous strains; T-Lymphocytes - drug effects; T-Lymphocytes - virology; Virology; Virus Replication - drug effects; Viruses; HIV-1 virus; Cytokine; Retroviridae; Host virus relation; Virus; Chemokine; Infectivity; Lentivirinae; Human immunodeficiency virus; Antagonist; Inhibition; Macrophage; Biological receptor
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.276.5310.276

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.