16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

THE MECHANISM OF HIV-1 ESCAPE FROM SMALL MOLECULE CCR5 ANTAGONISTS

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. MoAa0105

Pugach P., Kuhmann S., Ketas T., Moore J.P.
Weill Medical College of Cornell University, Microbiology and Immunology, New York, United States

BACKGROUND: CCR5 is the principal coreceptor used by the strains of HIV-1 that dominate early infection, and is a major target for development of a new drug class. Two small molecule CCR5 inhibitors, Maraviroc and Vicriviroc, are now in advanced clinical trials in HIV-infected people, and have demonstrated antiviral efficacy. To date, escape from them has not been demonstrated in vivo, but it can be anticipated.

METHODS: We have studied how HIV-1 escapes from small molecule CCR5 inhibitors in vitro, by creating resistant viruses and studying their properties.

RESULTS: We report that the drug-resistant viruses have acquired the ability to utilize CCR5 in its inhibitor-bound form. Thus the viruses resistant to the small molecule inhibitors are sensitive to inhibition by PSC-RANTES, but they become significantly resistant to this chemokine derivative when a small molecule inhibitor is also present. In single-round replication assays the drug escape variants exhibit characteristic resistance "plateaus" (e.g., at a maximum of 80% inhibition).

CONCLUSIONS: We interpret these findings to indicate that the resistant viruses are utilizing CCR5 receptors to which the small molecule have already bound in a way that blocks PSC-RANTES binding. The appearance of "plateaus" of incomplete resistance suggests that these viruses utilize drug-bound CCR5 less efficiently than drug-free receptors.

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2006-08-13
MoAa0105

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