title: CCR5 antibodies HGS004 and HGS101 preferentially inhibit drug-bound CCR5 infection and restore drug sensitivity of Maraviroc-resistant HIV-1 in primary cells.
abstract: R5 HIV-1 strains resistant to the CCR5 antagonist Maraviroc (MVC) can use drug-bound CCR5. We demonstrate that MVC-resistant HIV-1 exhibits delayed kinetics of coreceptor engagement and fusion during drug-bound versus free CCR5 infection of cell lines. Antibodies directed against the second extracellular loop (ECL2) of CCR5 had greater antiviral activity against MVC-bound compared to MVC-free CCR5 infection. However, in PBMCs, only ECL2 CCR5 antibodies HGS004 and HGS101, but not 2D7, inhibited infection by MVC resistant HIV-1 more potently with MVC-bound than with free CCR5. In addition, HGS004 and HGS101, but not 2D7, restored the antiviral activity of MVC against resistant virus in PBMCs. In flow cytometric studies, CCR5 binding by the HGS mAbs, but not by 2D7, was increased when PBMCs were treated with MVC, suggesting MVC increases exposure of the relevant epitope. Thus, HGS004 and HGS101 have antiviral mechanisms distinct from 2D7 and could help overcome MVC resistance.
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Latinovic
authors.forename: Marvin
authors.initials: M
authors.lastname: Reitz
authors.forename: Nhut M
authors.initials: NM
authors.lastname: Le
authors.forename: James S
authors.initials: JS
authors.lastname: Foulke
authors.forename: Gerd
authors.initials: G
authors.lastname: Fätkenheuer
authors.forename: Clara
authors.initials: C
authors.lastname: Lehmann
authors.forename: Robert R
authors.initials: RR
authors.lastname: Redfield
authors.forename: Alonso
authors.initials: A
authors.lastname: Heredia
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D000906:Antibodies / Q000276:immunology*; D065100:CCR5 Receptor Antagonists; D002478:Cells, Cultured; D003510:Cyclohexanes / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D000077592:Maraviroc; D008826:Microbial Sensitivity Tests; D019713:Receptors, CCR5 / Q000276:immunology*; D014230:Triazoles / Q000494:pharmacology*; D053586:Virus Internalization
chemical_list: D019380:Anti-HIV Agents; D000906:Antibodies; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc