Received for publication February 12, 2007.
Revised March 23, 2007.
Accepted for publication March 28, 2007.

CCR5 SMALL MOLECULE ANTAGONISTS AND MONOCLONAL ANTIBODIES EXERT POTENT SYNERGISTIC ANTIVIRAL EFFECTS BY CO-BINDING TO THE RECEPTOR

Abstract

A panel of four CCR5 mAbs recognizing different epitopes on CCR5 was examined in CCR5-mediated cell-cell fusion assay, alone or in combination with a variety of small molecule CCR5 antagonists. While no antagonism was observed between any of the CCR5 inhibitors, surprisingly potent synergy was observed between CCR5 mAbs and antagonists, and the synergistic activity was confirmed in other antiviral assays. Strong synergy was also observed between CCR5 inhibitors and HIV fusion inhibitor enfuvirtide. There was no synergy observed between small molecule CCR5 inhibitors, however, potent synergy was observed between mAbs recognizing different parts of CCR5. In all synergistic combinations, greater synergy was achieved at higher percent inhibition levels. A negative correlation was found between the degree of synergy between the two classes of CCR5 inhibitors and the ability to compete each other for binding to the receptor. For example, the greatest synergy was observed between mAb ROAb13 and small molecule inhibitor maraviroc which did not interfere with each other's binding to CCR5; while no synergy was found between mAb 45523 and maraviroc which compete for binding to CCR5. In addition, in contrast to a recent report, the CCR5 inhibitors tested here were found to inhibit the same stage of HIV entry. Based on the data presented here we hypothesize that CCR5 inhibitors exert synergistic antiviral actions through a co-binding mechanism.

Key words: Receptor binding studies, Antiviral drugs

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