Epitope switching as a novel escape mechanism of HIV to CCR5 monoclonal antibodies.
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.
Jekle
Andreas
A
Roche Palo Alto LLC, 3431 Hillview Ave., Palo Alto, CA 94304, USA. andreas.jekle@roche.com
Chhabra
Milloni
M
Lochner
Adriane
A
Meier
Sonja
S
Chow
Eugene
E
Brandt
Michael
M
Sankuratri
Surya
S
Cammack
Nick
N
Heilek
Gabrielle
G
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*
D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D000939:Epitopes; D019713:Receptors, CCR5