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02666 PSC-RANTES: DEVELOPMENT OF A POTENT HIV ENTRY INHIBITOR FOR USE AS A VAGINAL MICROBICIDE Hartley Oliver* We are currently developing microbicides that prevent HIV infection through blockade of a chemokine receptor, CCR5, which is used by the virus during entry into target cells. Our work is based on the development of analogues of RANTES, a natural protein ligand of CCR5. RANTES itself has been noted for its capacity to block infection by viruses that use CCR5, but some of our analogues are several orders of magnitude more potent. The remarkable anti-HIV activity of these analogues appears to be due to a novel inhibitory mechanism: they induce prolonged intracellular sequestration of the receptor, making it unavailable to the virus for entry. Although they are proteins, our RANTES analogues are stable for months in solution at ambient temperature. They also retain activity when formulated in hydroxymethylcellulose gel. Our recent experiments show that our most potent analogue, PSC-RANTES, fully protects female macaques from vaginal transmission of a CCR5-tropic SHIV. Taken together, these results suggest that PSC-RANTES is a promising candidate for development as a vaginal microbicide. Dr. Oliver Hartley |
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