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

doi:10.1128/JVI.74.14.6418-6424.2000

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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^, 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 signalsthrough chemokine coreceptors on macrophages was examined by measuringthe ability of recombinant envelope proteins to mobilize intracellularcalcium stores. Both HIV and SIV envelopes mobilized calcium viainteractions with CCR5. The kinetics of these responses were similarto those observed when macrophages were treated with MIP-1 $beta$ . Distinctdifferences in the capacity of envelopes to mediate calcium mobilizationwere observed. Envelopes derived from viruses capable of replicatingin macrophages mobilized relatively high levels of calcium, whileenvelopes derived from viruses incapable of replicating in macrophagesmobilized relatively low levels of calcium. The failure to efficientlymobilize calcium was not restricted to envelopes derived fromCXCR4-utilizing isolates but also included envelopes derived fromCCR5-utilizing isolates that fail to replicate in macrophages.We characterized one CCR5-utilizing isolate, 92MW959, which enteredmacrophages but failed to replicate. A recombinant envelope derivedfrom this virus mobilized low levels of calcium. When macrophageswere inoculated with 92MW959 in the presence of MIP-1 $alpha$ , viralreplication was observed, indicating that a CC chemokine-mediatedsignal provided the necessary stimulus to allow the virus to completeits replication cycle. Although the role that envelope-CCR5 signaltransduction plays in viral replication is not yet understood,it has been suggested that envelope-mediated signals facilitateearly postfusion events in viral replication. The data presentedhere are consistent with this hypothesis and suggest that thedifferential capacity of viral envelopes to signal through CCR5may influence their ability to replicate inmacrophages.

^* 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.

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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