The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/7/139/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 1, July 7, 1997 139-146

Articles

HIV Coreceptor Downregulation as Antiviral Principle: SDF-1{alpha}–dependent Internalization of the Chemokine Receptor CXCR4 Contributes to Inhibition of HIV Replication

Ali Amara*, Sylvie Le Gall{ddagger}, Olivier Schwartz{ddagger}, Jean Salamero§, Monica Montes||, Pius Loetscher, Marco Baggiolini, Jean-Louis Virelizier*, and Fernando Arenzana-Seisdedos*

From the * Unité d'Immunologie Virale and {ddagger} Laboratoire Rétrovirus et Transfert Génétique, Institut Pasteur, 75724 Paris, Cedex 15, France; § Laboratoire Mécanismes Moléculaires du Transport Intracellulaire, Centre National de la Recherche Scientifique UMR 144, Institut Curie, 75248 Paris Cedex 05, France; || Laboratoire d'Immunologie Cellulaire, Centre National de la Recherche Scientifique URA 625, CERVI, 75013 Paris, France; and Theodor Kocher Institute, University of Bern, CH-3000 Bern 9, Switzerland

Ligation of CCR5 by the CC chemokines RANTES, MIP-1{alpha} or MIP-1β, and of CXCR4 by the CXC chemokine SDF-1{alpha}, profoundly inhibits the replication of HIV strains that use these coreceptors for entry into CD4+ T lymphocytes. The mechanism of entry inhibition is not known. We found a rapid and extensive downregulation of CXCR4 by SDF-1{alpha} and of CCR5 by RANTES or the antagonist RANTES(9-68). Confocal laser scanning microscopy showed that CCR5 and CXCR4, after binding to their ligands, are internalized into vesicles that qualify as early endosomes as indicated by colocalization with transferrin receptors. Internalization was not affected by treatment with Bordetella pertussis toxin, showing that it is independent of signaling via Gi-proteins. Removal of SDF-1{alpha} led to rapid, but incomplete surface reexpression of CXCR4, a process that was not inhibited by cycloheximide, suggesting that the coreceptor is recycling from the internalization pool. Deletion of the COOH-terminal, cytoplasmic domain of CXCR4 did not affect HIV entry, but prevented SDF-1{alpha}–induced receptor downregulation and decreased the potency of SDF-1{alpha} as inhibitor of HIV replication. Our results indicate that the ability of the coreceptor to internalize is not required for HIV entry, but contributes to the HIV suppressive effect of CXC and CC chemokines.

Address correspondence to Fernando Arenzana-Seisdedos, Unité d'Immunologie Virale, Institut Pasteur, 75724 Paris, Cedex 15, France.

A. Amara and S. Le Gall contributed equally to this work.


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