title: A small-molecule inhibitor directed against the chemokine receptor CXCR4 prevents its use as an HIV-1 coreceptor.
abstract: The chemokine receptor CXCR4 is the major coreceptor used for cellular entry by T cell- tropic human immunodeficiency virus (HIV)-1 strains, whereas CCR5 is used by macrophage (M)-tropic strains. Here we show that a small-molecule inhibitor, ALX40-4C, inhibits HIV-1 envelope (Env)-mediated membrane fusion and viral entry directly at the level of coreceptor use. ALX40-4C inhibited HIV-1 use of the coreceptor CXCR4 by T- and dual-tropic HIV-1 strains, whereas use of CCR5 by M- and dual-tropic strains was not inhibited. Dual-tropic viruses capable of using both CXCR4 and CCR5 were inhibited by ALX40-4C only when cells expressed CXCR4 alone. ALX40-4C blocked stromal-derived factor (SDF)-1alpha-mediated activation of CXCR4 and binding of the monoclonal antibody 12G5 to cells expressing CXCR4. Overlap of the ALX40-4C binding site with that of 12G5 and SDF implicates direct blocking of Env interactions, rather than downregulation of receptor, as the mechanism of inhibition. Thus, ALX40-4C represents a small-molecule inhibitor of HIV-1 infection that acts directly against a chemokine receptor at the level of Env-mediated membrane fusion.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Doranz
authors.forename: K
authors.initials: K
authors.lastname: Grovit-Ferbas
authors.forename: M P
authors.initials: MP
authors.lastname: Sharron
authors.forename: S H
authors.initials: SH
authors.lastname: Mao
authors.forename: M B
authors.initials: MB
authors.lastname: Goetz
authors.forename: E S
authors.initials: ES
authors.lastname: Daar
authors.forename: R W
authors.initials: RW
authors.lastname: Doms
authors.forename: W A
authors.initials: WA
authors.lastname: O'Brien
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D016399:Lymphoma, T-Cell; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013601:T-Lymphocytes / Q000821:virology; D014407:Tumor Cells, Cultured
chemical_list: D019380:Anti-HIV Agents; C094365:N-alpha-acetyl-nona-D-arginine amide acetate; D009842:Oligopeptides; D019718:Receptors, CXCR4