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J. Virol., 09 1997, 6305-6314, Vol 71, No. 9
Copyright © 1997, American Society for Microbiology

Two distinct CCR5 domains can mediate coreceptor usage by human immunodeficiency virus type 1

BJ Doranz, ZH Lu, J Rucker, TY Zhang, M Sharron, YH Cen, ZX Wang, HH Guo, JG Du, MA Accavitti, RW Doms and SC Peiper
Department of Pathology, University of Pennsylvania, Philadelphia 19104, USA.

The chemokine receptor CCR5 is the major fusion coreceptor for macrophage-tropic strains of human immunodeficiency virus type 1 (HIV- 1). To define the structures of CCR5 that can support envelope (Env)- mediated membrane fusion, we analyzed the activity of homologs, chimeras, and mutants of human CCR5 in a sensitive gene reporter cell- cell fusion assay. Simian, but not murine, homologs of CCR5 were fully active as HIV-1 fusion coreceptors. Chimeras between CCR5 and divergent chemokine receptors demonstrated the existence of two distinct regions of CCR5 that could be utilized for Env-mediated fusion, the amino- terminal domain and the extracellular loops. Dual-tropic Env proteins were particularly sensitive to alterations in the CCR5 amino-terminal domain, suggesting that this domain may play a pivotal role in the evolution of coreceptor usage in vivo. We identified individual residues in both functional regions, Asp-11, Lys-197, and Asp-276, that contribute to coreceptor function. Deletion of a highly conserved cytoplasmic motif rendered CCR5 incapable of signaling but did not abrogate its ability to function as a coreceptor, implying the independence of fusion and G-protein-mediated chemokine receptor signaling. Finally, we developed a novel monoclonal antibody to CCR5 to assist in future studies of CCR5 expression.


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