title: Multifaceted mechanisms of HIV inhibition and resistance to CCR5 inhibitors PSC-RANTES and Maraviroc.
abstract: Small-molecule CCR5 antagonists, such as maraviroc (MVC), likely block HIV-1 through an allosteric, noncompetitive inhibition mechanism, whereas inhibition by agonists such as PSC-RANTES is less defined and may involve receptor removal by cell surface downregulation, competitive inhibition by occluding the HIV-1 envelope binding, and/or allosteric effects by altering CCR5 conformation. We explored the inhibitory mechanisms of maraviroc and PSC-RANTES by employing pairs of virus clones with differential sensitivities to these inhibitors. Intrinsic PSC-RANTES-resistant virus (YA versus RT) or those selected in PSC-RANTES treated macaques (M584 versus P3-4) only displayed resistance in multiple-cycle assays or with a CCR5 mutant that cannot be downregulated. In single-cycle assays, these HIV-1 clones displayed equal sensitivity to PSC-RANTES inhibition, suggesting effective receptor downregulation. Prolonged PSC-RANTES exposure resulted in desensitization of the receptor to internalization such that increasing virus concentration (substrate) could saturate the receptors and overcome PSC-RANTES inhibition. In contrast, resistance to MVC was observed with the MVC-resistant HIV-1 (R3 versus S2) in both multiple- and single-cycle assays and with altered virus concentrations, which is indicative of allosteric inhibition. MVC could also mediate inhibition and possibly resistance through competitive mechanisms.
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lobritz
authors.forename: Annette N
authors.initials: AN
authors.lastname: Ratcliff
authors.forename: Andre J
authors.initials: AJ
authors.lastname: Marozsan
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Dudley
authors.forename: John C
authors.initials: JC
authors.lastname: Tilton
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Arts
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D018946:Chemokine CCL5 / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D003510:Cyclohexanes / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015536:Down-Regulation; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008251:Macaca; D000077592:Maraviroc; D008826:Microbial Sensitivity Tests / Q000379:methods; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D003510:Cyclohexanes; C492865:RANTES, N(alpha)-(n-nonanoyl)-desSer(1)-(thioproline(2),cyclohexylglycine(3))-; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc