Quantifying the relationship between HIV-1 susceptibility to CCR5 antagonists and virus affinity for antagonist-occupied co-receptor.
Previous studies have demonstrated that HIV-1 develops resistance to CCR5 antagonists by gaining the ability to use drug-occupied co-receptor. However, the effects of CCR5 antagonists on the affinity of virus-co-receptor interactions have been difficult to quantify. We developed a pharmacological model for allosteric interaction at G-protein coupled receptors to analyze the effect of different CCR5 antagonists on infection by three laboratory adapted viruses with low, moderate and high susceptibility to the inhibitors. Infection data for these viruses fitted a model in which susceptibility to inhibition by CCR5 antagonists was directly related to fold reduction in virus affinity for CCR5. Dissociation constants for CCR5 antagonists calculated from the modeled data were consistent with values obtained by standard methods, suggesting that this approach can quantify pharmacologically relevant changes in co-receptor:ligand affinity in the context of infection of whole cells by authentic HIV-1 particles.
Schering-Plough Research Institute, Department of Biological Sciences- VIROLOGY, K-15-4950, Kenilworth, Building K-15-4, Mailstop 4950, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Peter J
PJ
Buontempo
Lisa
L
Wojcik
Catherine A
CA
Buontempo
Robert A
RA
Ogert
Julie M
JM
Strizki
John A
JA
Howe
Robert
R
Ralston
D000494:Allosteric Regulation; D019380:Anti-HIV Agents / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D043562:Receptors, G-Protein-Coupled