HIV Drug Resistance: Selection, Persistence, and Impact of Response
Thursday, 10 am - 12:30 pm
Presentation Time: 10:00 am
Background: CCR5-tropic HIV-1 variants, selected during prolonged serial passage of virus in the presence of HIV co-receptor antagonists, appear to use compound-bound receptor to infect target cells. Previously published studies suggest that all small molecule CCR5 antagonists bind to a similar region of the receptor, raising the possibility of generalized class-resistance.
Methods: We have located the binding site of UK-427,857 and structurally related compounds within CCR5, using a panel of site-directed mutants and a 3-dimensional model based on homology with bovine rhodopsin. We also measured their potency against R5 viruses, including CCR5-tropic variants of primary HIV-1 isolates that are highly resistant to UK-427,857 (427res).
Results: All the antagonists bind CCR5 in a pocket formed by the trans-membrane helices and extracellular loop 2 (ECL2), centered on an ionic interaction with E283 and a hydrophobic interaction with Y108. The compounds have low nanomolar potency against the R5 lab-adapted HIV-1 strain, Ba-L, and are active against the wild type R5 primary isolates, CC1/85 and RU570. Compounds that contain a triazole moiety were inactive against 427res variants of CC1/85 and RU570. In contrast, compounds where the triazole is replaced by an imidazopiperidine retained activity.
Conclusions: Substitution of a key functional group in a series of structurally related HIV co-receptor antagonists leads to biologically significant changes in the way 427res viruses interact with compound-bound CCR5. It appears that subtle differences in the occupation of the binding pocket, in particular around the ECL2 interface, enable some compounds to block replication of 427res strains. Encouragingly, our data indicate that resistance to an HIV co-receptor antagonist will not necessarily lead to drug-class resistance.
Keywords: CCR5; resistance; entry