Maraviroc (UK-427,857)-resistant HIV-1 variants Are Sensitive to CCR5 Antagonists and Enfuvirtide

M Westby, J Mori, C Smith-Burchnell, M Lewis, M Mosley, F Perruccio, R Mansfield, P Dorr and MPerros Pfizer Global R&D, Sandwich, UK

Maraviroc (MVC, UK-427,857) is a CCR5 antagonist in late stage clinical development for treatment of HIV-1 infection. CCR5 antagonists inhibit virus entry but differ from the licensed fusion inhibitor, enfuvirtide (T-20), in that they bind to the host cell and not the virus envelope. We have tested MVC-resistant HIV-1 variants against other entry inhibitors and modeled the binding of these compounds to CCR5 to help explain how they function as antiviral agents.

MVC-resistant variants were tested for their susceptibility to other CCR5 antagonists and entry inhibitors, both in replication-competent antiviral assays and using the PhenoSense Entry assay. Binding of compounds to CCR5 was also modeled using published information, in an attempt to explain the findings from the antiviral assays.

Results

MVC-resistant HIV-1 variants were susceptible to the CCR5 antagonists, SCH-C, SCH-D and GK873140. Modeling studies showed that all compounds bound in a similar pocket of CCR5 within the trans-membrane region. The viruses were also sensitive to T-20; consistent with this there were no differences between the HR1 or HR2 domains of MVC-sensitive and resistant variants.

Conclusions

Maraviroc did not select in vitro for HIV-1 variants cross-resistant to other entry inhibitors, notably other CCR5 antagonists. We propose that SCH-C, SCH-D and GK873140 bind to similar regions of CCR5 to Maraviroc but hold the receptor in different conformations that are sufficient to inhibit entry of MVC-resistant variants.

07/18/05

Reference
M Westby and others. Maraviroc (UK-427,857)-resistant HIV-1 variants, selected by serial passage, are sensitive to CCR5 antagonists and T-20. Abstract 65 (poster). XIV International HIV Drug Resistance Workshop IC Report: Basic Principles and Clinical Implications. June 7-11, 2005. Québec City, Québec, Canada. [Antiviral Therapy 10, Supplement 1 S72].

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