Evolution of HIV-1 coreceptor usage through interactions with distinct CCR5 and CXCR4 domains.
Publication/Presentation Date
6-10-1997
Abstract
The chemokine receptor CXCR4 functions as a fusion coreceptor for T cell tropic and dual-tropic HIV-1 strains. To identify regions of CXCR4 that are important for coreceptor function, CXCR4-CXCR2 receptor chimeras were tested for the ability to support HIV-1 envelope (env) protein-mediated membrane fusion. Receptor chimeras containing the first and second extracellular loops of CXCR4 supported fusion by T tropic and dual-tropic HIV-1 and HIV-2 strains and binding of a monoclonal antibody to CXCR4, 12G5, that blocks CXCR4-dependent infection by some virus strains. The second extracellular loop of CXCR4 was sufficient to confer coreceptor function to CXCR2 for most virus strains tested but did not support binding of 12G5. Truncation of the CXCR4 cytoplasmic tail or mutation of a conserved DRY motif in the second intracellular loop did not affect coreceptor function, indicating that phosphorylation of the cytoplasmic tail and the DRY motif are not required for coreceptor function. The results implicate the involvement of multiple CXCR4 domains in HIV-1 coreceptor function, especially the second extracellular loop, though the structural requirements for coreceptor function were somewhat variable for different env proteins. Finally, a hybrid receptor in which the amino terminus of CXCR4 was replaced by that of CCR5 was active as a coreceptor for M tropic, T tropic, and dual-tropic env proteins. We propose that dual tropism may evolve in CCR5-restricted HIV-1 strains through acquisition of the ability to utilize the first and second extracellular loops of CXCR4 while retaining the ability to interact with the CCR5 amino-terminal domain.
Volume
94
Issue
12
First Page
6426
Last Page
6431
ISSN
0027-8424
Published In/Presented At
Lu, Z., Berson, J. F., Chen, Y., Turner, J. D., Zhang, T., Sharron, M., Jenks, M. H., Wang, Z., Kim, J., Rucker, J., Hoxie, J. A., Peiper, S. C., & Doms, R. W. (1997). Evolution of HIV-1 coreceptor usage through interactions with distinct CCR5 and CXCR4 domains. Proceedings of the National Academy of Sciences of the United States of America, 94(12), 6426–6431. https://doi.org/10.1073/pnas.94.12.6426
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
9177234
Department(s)
Administration and Leadership
Document Type
Article