The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/4/1215/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 8, April 20, 1998 1215-1224

Articles

Aminooxypentane-RANTES Induces CCR5 Internalization but Inhibits Recycling: A Novel Inhibitory Mechanism of HIV Infectivity

Matthias Mack*, Bruno Luckow*, Peter J. Nelson*, Josef Cihak{ddagger}, Graham Simmons§, Paul R. Clapham§, Nathalie Signoret||, Mark Marsh||, Manfred Stangassinger{ddagger}, Fréderic Borlat, Timothy N.C. Wells, Detlef Schlöndorff*, and Amanda E.I. Proudfoot

From the * Medizinische Poliklinik, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany; the {ddagger} Institute for Animal Physiology, University of Munich, 80539 Munich, Germany; the § Section of Virology, Chester Beatty Laboratories, Institute of Cancer Research, London SW3 6JB, United Kingdom; the || Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, United Kingdom; and the Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development SA, 1228 Plan-les-Ouates, Geneva, Switzerland

CCR5, a chemokine receptor expressed on T cells and macrophages, is the principal coreceptor for M-tropic HIV-1 strains. Recently, we described an NH2-terminal modification of the CCR5 ligand regulated on activation, normal T cell expressed and secreted (RANTES), aminooxypentane-RANTES (AOP-RANTES), that showed potent inhibition of macrophage infection by HIV-1 under conditions where RANTES was barely effective. To investigate the mechanism of AOP-RANTES inhibition of HIV infectivity we examined the surface expression of CCR5 using a monoclonal anti-CCR5 antibody, MC-1. We demonstrate that AOP-RANTES rapidly caused >90% decrease in cell surface expression of CCR5 on lymphocytes, monocytes/ macrophages, and CCR5 transfected Chinese hamster ovary (CHO) cells. RANTES also caused a loss of cell surface CCR5, although its effect was less than with AOP-RANTES. Significantly, AOP-RANTES inhibited recycling of internalized CCR5 to the cell surface, whereas RANTES did not. When peripheral blood mononuclear cells are cultured for prolonged periods of time in the presence of RANTES, CCR5 expression is comparable to that seen on cells treated with control medium, whereas there is no CCR5 surface expression on cells cultured in the presence of AOP-RANTES. Immunofluorescence indicated that both AOP-RANTES and RANTES induced downmodulation of cell surface CCR5, and that the receptor was redistributed into endocytic organelles containing the transferrin receptor. When RANTES was removed, the internalized receptor was recycled to the cell surface; however, the receptor internalized in the presence of AOP-RANTES was retained in endosomes. Using human osteosarcoma (GHOST) 34/CCR5 cells, the potency of AOP-RANTES and RANTES to inhibit infection by the M-tropic HIV-1 strain, SF 162, correlated with the degree of downregulation of CCR5 induced by the two chemokines. These differences between AOP-RANTES and RANTES in their effect on receptor downregulation and recycling suggest a mechanism for the potent inhibition of HIV infection by AOP-RANTES. Moreover, these results support the notion that receptor internalization and inhibition of receptor recycling present new targets for therapeutic agents to prevent HIV infection.

Address correspondence to Amanda Proudfoot, Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland. Phone: 41-22-70-69-800; Fax: 41-22-794-69-65; E-mail: aep6830{at}ggr.co.uk, and Detlef Schlöndorff, Medizinische Poliklinik, Ludwig-Maximilians-University, Pettenkoferstr. 8a, 80336 Munich, Germany. Phone: 49-89-51-60-3500; Fax: 49-89-51-60-4439; E-mail: sdorff{at}pk-1.med.uni-muenchen.de

P.R. Clapham and G. Simmons were supported by the Medical Research Council (UK) and B. Luckow and P.J. Nelson were supported by grants from the Deutsche Forschungsgemeinschaft (Lu 612/1-1 and SFB 464).

The present address of F. Borlat and T.N.C. Wells is Sereno Pharmaceutical Research Institute, 14 Chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland.

1 Abbreviations used in this paper: AOP, aminooxypentane; BM, binding medium; CHO, Chinese hamster ovary; MIP, macrophage inflammatory protein; RANTES, regulated on activation, normal T cell expressed and secreted; TfR, transferrin receptor.


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