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Journal of Virology, July 2000, p. 6418-6424, Vol. 74, No. 14
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

CCR5 Signal Transduction in Macrophages by Human Immunodeficiency Virus and Simian Immunodeficiency Virus Envelopes

James Arthos,1,* Andrea Rubbert,1,dagger Ronald L. Rabin,2 Claudia Cicala,1 Elizabeth Machado,1 Kathryne Wildt,1 Meredith Hanbach,1 Tavis D. Steenbeke,1 Ruth Swofford,2 Joshua M. Farber,2 and Anthony S. Fauci1

Laboratory of Immunoregulation1 and Laboratory of Clinical Investigation,2 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

Received 28 December 1999/Accepted 14 April 2000

The capacity of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) envelopes to transduce signals through chemokine coreceptors on macrophages was examined by measuring the ability of recombinant envelope proteins to mobilize intracellular calcium stores. Both HIV and SIV envelopes mobilized calcium via interactions with CCR5. The kinetics of these responses were similar to those observed when macrophages were treated with MIP-1beta . Distinct differences in the capacity of envelopes to mediate calcium mobilization were observed. Envelopes derived from viruses capable of replicating in macrophages mobilized relatively high levels of calcium, while envelopes derived from viruses incapable of replicating in macrophages mobilized relatively low levels of calcium. The failure to efficiently mobilize calcium was not restricted to envelopes derived from CXCR4-utilizing isolates but also included envelopes derived from CCR5-utilizing isolates that fail to replicate in macrophages. We characterized one CCR5-utilizing isolate, 92MW959, which entered macrophages but failed to replicate. A recombinant envelope derived from this virus mobilized low levels of calcium. When macrophages were inoculated with 92MW959 in the presence of MIP-1alpha , viral replication was observed, indicating that a CC chemokine-mediated signal provided the necessary stimulus to allow the virus to complete its replication cycle. Although the role that envelope-CCR5 signal transduction plays in viral replication is not yet understood, it has been suggested that envelope-mediated signals facilitate early postfusion events in viral replication. The data presented here are consistent with this hypothesis and suggest that the differential capacity of viral envelopes to signal through CCR5 may influence their ability to replicate in macrophages.


* Corresponding author. Mailing address: NIH, Bldg. 10, Rm. 6A-08, 10 Center Dr., Bethesda, MD 20892. Phone: (301) 402-3547. Fax: (301) 480-5244. E-mail: jarthos{at}nih.gov.

dagger Present address: Department of Clinical Medicine, University of Cologne, Cologne, Germany.


Journal of Virology, July 2000, p. 6418-6424, Vol. 74, No. 14
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.



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