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AIDS 2006; Toronto, Canada; August 13-18, 2006

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The Body Covers: The XVI International AIDS Conference
Aplaviroc's Potency Against HIV Is Linked to Its Slow Dissociation From the CCR5 Receptor

August 17, 2006

Despite the decision by GlaxoSmithKline (Glaxo) to halt further clinical study of aplaviroc (GSK873140) in treatment-naive patients due to reports of hepatotoxicity in phase 2 trials, research on this and other CCR5 antagonists continues with the hope of soon bringing these agents to market. CCR5 antagonists inhibit protein-protein interactions between the HIV-1 envelope protein gp120 and the CCR5 receptor on CD4+ T cells via a proposed allosteric mechanism. In other words, CCR5 antagonists do not directly interact with the CCR5 binding site to block HIV-1 binding, but instead interact with another region of CCR5 that induces a conformational change in the CCR5 binding site. Since HIV-1 cannot use the CCR5 pathway when an antagonist is bound, the viral entry cascade and subsequent infection by CCR5-tropic HIV-1 is prevented.

Previous studies by Patrick Dorr and others showed that the ability of experimental CCR5 antagonists to inhibit HIV-1-induced membrane fusion and viral replication was only partially explained by their affinity for the receptor and their ability to prevent gp120 binding. A weak correlation between the inhibition of binding and the prevention of fusion raised the interesting possibility that the role of CCR5 antagonists in viral entry is not solely limited to gp120 binding and that perhaps the agents also affect viral entry at a step subsequent to viral attachment.

CCR5 receptor occupancy by Glaxo's compound aplaviroc correlates well with its antiretroviral activity. Receptor occupancy is crucial to the success of CCR5 antagonists, since binding of the drugs to the CD4+ T cell prevents HIV binding. A new study presented at the XVI International AIDS Conference examined the relationship between aplaviroc's slow dissociation rate from CCR5 and its potent anti-HIV activity,1 thus catapulting Dorr's research into the clinical realm.

In Dr. Shibayama's experiments for Ono Pharmaceuticals (in Japan) and Glaxo, flow cytometric analysis was used to determine the duration of in vivo blood receptor occupancy after intraperitoneal administration of aplaviroc in mice injected with fluorescently labeled murine cells expressing human CCR5.2 Aplaviroc showed more persistent binding to and slower dissociation from human CCR5 versus monkey CCR5 both in vitro and in vivo. Ca2+ response curves suggest that an allosteric mechanism was at play in both monkeys and humans. A single amino acid -- isoleucine-198 in transmembrane region-5 -- was found to be responsible for the slow dissociation rate in humans; mutating this amino acid in the human CCR5 protein (i.e., I198M) resulted in a dissociation rate similar to that observed in monkeys. The dissociation constant (koff/kon) for human CCR5 is about 10-fold lower than that for monkey CCR5 and the human CCR5 I198M mutant, indicating that the binding mechanism of aplaviroc does not follow the law of mass action. (If the law of mass action applies, then binding by one ligand will not affect that of another ligand.) The Scatchard plot of aplaviroc binding to human CCR5 showed a convex curve and the Hill coefficient was 1.7, both of which indicate cooperative interaction between aplaviroc and human CCR5.

These results help illuminate the binding mechanism of aplaviroc, which involves positive cooperativity with an allosteric mechanism. Aplaviroc binds to an allosteric site within CCR5 and induces a conformational change. This change then mediates communication between CCR5 dimer partners -- a process that occurs most efficiently when I198 is present -- and results in persistent receptor occupancy. More studies will be needed to evaluate whether other CCR5 antagonists utilize this mechanism for long-lasting receptor occupancy. For now, however, we have a better understanding of aplaviroc's potent activity and future potential.


  1. Dorr PK, Corbau R, Pickford C, et al. Evaluation of the mechanism underlying the anti-HIV activity of a series of experimental CCR5 antagonists. In: Program and abstracts of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; September 14-17, 2003; Chicago, Ill. Abstract F-1466.

  2. Shibayama S, Tanihiro T, Takeda K, et al. Cooperative interaction between a CCR5 antagonist, aplaviroc (873140/ONO-4128), and human CCR5 with allosteric mechanism. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THAA0305.

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