title: Epitope switching as a novel escape mechanism of HIV to CCR5 monoclonal antibodies.
abstract: In passaging experiments, we isolated HIV strains resistant to MAb3952, a chemokine (C-C motif) receptor 5 (CCR5) monoclonal antibody (MAb) that binds to the second extracellular domain (extracellular loop 2 [ECL-2]) of CCR5. MAb3952-resistant viruses remain CCR5-tropic and are cross-resistant to a second ECL-2-specific antibody. Surprisingly, MAb3952-resistant viruses were more susceptible to RoAb13, a CCR5 antibody binding to the N terminus of CCR5. Using CCR5 receptor mutants, we show that MAb3952-resistant virus strains preferentially use the N terminus of CCR5, while the wild-type viruses preferentially use ECL-2. We propose this switch in the CCR5 binding site as a novel mechanism of HIV resistance.
authors.affiliation: Roche Palo Alto LLC, 3431 Hillview Ave., Palo Alto, CA 94304, USA. andreas.jekle@roche.com
authors.forename: Andreas
authors.initials: A
authors.lastname: Jekle
authors.forename: Milloni
authors.initials: M
authors.lastname: Chhabra
authors.forename: Adriane
authors.initials: A
authors.lastname: Lochner
authors.forename: Sonja
authors.initials: S
authors.lastname: Meier
authors.forename: Eugene
authors.initials: E
authors.lastname: Chow
authors.forename: Michael
authors.initials: M
authors.lastname: Brandt
authors.forename: Surya
authors.initials: S
authors.lastname: Sankuratri
authors.forename: Nick
authors.initials: N
authors.lastname: Cammack
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Heilek
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use*; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D024882:Drug Resistance, Viral / Q000235:genetics; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006678:HIV / Q000187:drug effects* / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019713:Receptors, CCR5 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D000939:Epitopes; D019713:Receptors, CCR5