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Dual-Tropic Recombinant Chimeric Chemokines Directed against Both M-Tropic (R5) and T-Tropic (X4) HIVs S. K. ARYA*, C. GINSBERG, A. DAVIS-WARREN, N. MAKHZANI, and J. D'ACOSTA. NCI NIH, Bethesda, MD To achieve effective control of HIV infection, a dual-tropic chemokine directed against both M-tropic (R5) and T-tropic (X4) HIVs will be needed. It is clear that HIV undergoes transition from the relatively mild M-tropic to the more virulent T-tropic HIV during the course of infection. There is evidence that a blockade of only CCR5 promotes the emergence of X4 viruses, and that the use of CC chemokine enhances infection with X4 viruses, and conversely, CXC chemokine enhances infection with R5 viruses. For understanding the three-way interaction between the receptor, the viral envelope, and the chemokine, we have formulated two models: one in which the viral envelope competes with the chemokine for the same site on the receptor and the other in which the two ligands occupy distinct, perhaps interacting sites. There is now increasing evidence that the binding sites on the receptor for the viral envelope for fusion and the chemokine for signal transduction are not identical, though they may be overlapping. Our effort to create dual-tropic chimeric chemokines is based on the premise that minimal functional domains in CC (RANTES) and CXC (SDF-1) chemokines exist, that these domains can be brought together on a single molecule that maintains its native conformation, and that these domains can be manipulated to achieve a balance of effectiveness against M- and T-tropic HIVs. Mole per mole, RANTES is 10-fold more effective against its target virus than SDF-1 is against its target. We have delineated structural motifs of RANTES important for its antiviral activity and also for its biological stability and intracellular transport. Among the chimeras, one chimera provides strong support for the feasibility of creating a dual-tropic molecule. This chimera consists of the RANTES backbone with the part of the b–1 domain replaced with the corresponding domain from SDF-1. This chimera displays a switch in its phenotype and forms the basis for second generation chimeras with permuted single amino acid substitutions. Key Words: chemokines, chimera, HIV |
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© 7th
Conference on Retroviruses and Opportunistic Infections, |