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Science 11 April 1997:
Vol. 276. no. 5310, pp. 276 - 279
DOI: 10.1126/science.276.5310.276
Prev | Table of Contents

Reports

Potent Inhibition of HIV-1 Infectivity in Macrophages and Lymphocytes by a Novel CCR5 Antagonist

Graham Simmons, Paul R. Clapham, * Laurent Picard, Robin E. Offord, dagger Mette M. Rosenkilde, Thue W. Schwartz, Raphaële Buser, Timothy N. C. Wells, Amanda E. I. Proudfoot *

The chemokine receptors CXCR4 and CCR5 have recently been shown to act as coreceptors, in concert with CD4, for human immunodeficiency virus-type 1 (HIV-1) infection. RANTES and other chemokines that interact with CCR5 and block infection of peripheral blood mononuclear cell cultures inhibit infection of primary macrophages inefficiently at best. If used to treat HIV-1-infected individuals, these chemokines could fail to influence HIV replication in nonlymphocyte compartments while promoting unwanted inflammatory side effects. A derivative of RANTES that was created by chemical modification of the amino terminus, aminooxypentane (AOP)-RANTES, did not induce chemotaxis and was a subnanomolar antagonist of CCR5 function in monocytes. It potently inhibited infection of diverse cell types (including macrophages and lymphocytes) by nonsyncytium-inducing, macrophage-tropic HIV-1 strains. Thus, activation of cells by chemokines is not a prerequisite for the inhibition of viral uptake and replication. Chemokine receptor antagonists like AOP-RANTES that achieve full receptor occupancy at nanomolar concentrations are strong candidates for the therapy of HIV-1-infected individuals.

G. Simmons, P. R. Clapham, L. Picard, Virology Group, Chester Beatty Laboratories, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
R. E. Offord, Départment de Biochimie Médicale, Centre Médical Universitaire, 9 Avenue de Champel, 1211 Geneva 4, Switzerland, and Gryphon Sciences, 250 East Grand Avenue, Suite 90, South San Francisco, CA 94080, USA.
M. M. Rosenkilde and T. W. Schwartz, Laboratory for Molecular Pharmacology, Rigshospitalet 6321, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
R. Buser, T. N. C. Wells, A. E. I. Proudfoot, Geneva Biomedical Research Institute, GlaxoWellcome Research and Development SA, 14 chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland.
*   To whom correspondence should be addressed.

dagger    To whom requests for AOP-RANTES should be sent.

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L. Lopalco, C. Barassi, C. Pastori, R. Longhi, S. E. Burastero, G. Tambussi, F. Mazzotta, A. Lazzarin, M. Clerici, and A. G. Siccardi (2000)
J. Immunol. 164, 3426-3433
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Differential Activation of CC Chemokine Receptors by AOP-RANTES.
J. Elsner, M. Mack, H. Bruhl, Y. Dulkys, D. Kimmig, G. Simmons, P. R. Clapham, D. Schlondorff, A. Kapp, T. N. C. Wells, et al. (2000)
J. Biol. Chem. 275, 7787-7794
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International Union of Pharmacology. XXII. Nomenclature for Chemokine Receptors.
P. M. Murphy, M. Baggiolini, I. F. Charo, C. A. Hebert, R. Horuk, K. Matsushima, L. H. Miller, J. J. Oppenheim, and C. A. Power (2000)
Pharmacol. Rev. 52, 145-176
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C-C Chemokine Receptor 3 Antagonism by the {beta}-Chemokine Macrophage Inflammatory Protein 4, a Property Strongly Enhanced by an Amino-Terminal Alanine-Methionine Swap.
R. J. B. Nibbs, T. W. Salcedo, J. D. M. Campbell, X.-T. Yao, Y. Li, B. Nardelli, H. S. Olsen, T. S. Morris, A. E. I. Proudfoot, V. P. Patel, et al. (2000)
J. Immunol. 164, 1488-1497
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A Highly Selective CC Chemokine Receptor (CCR)8 Antagonist Encoded by the Poxvirus Molluscum Contagiosum.
H. R. Luttichau, J. Stine, T. P. Boesen, A. H. Johnsen, D. Chantry, J. Gerstoft, and T. W. Schwartz (2000)
J. Exp. Med. 191, 171-180
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Soluble complexes of regulated upon activation, normal T cells expressed and secreted (RANTES) and glycosaminoglycans suppress HIV-1 infection but do not induce Ca2+ signaling.
J. M. Burns, G. K. Lewis, and A. L. DeVico (1999)
PNAS 96, 14499-14504
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Multiple Charged and Aromatic Residues in CCR5 Amino-terminal Domain Are Involved in High Affinity Binding of Both Chemokines and HIV-1 Env Protein.
C. Blanpain, B. J. Doranz, J. Vakili, J. Rucker, C. Govaerts, S. S. W. Baik, O. Lorthioir, I. Migeotte, F. Libert, F. Baleux, et al. (1999)
J. Biol. Chem. 274, 34719-34727
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Amino-terminally Modified RANTES Analogues Demonstrate Differential Effects on RANTES Receptors.
A. E. I. Proudfoot, R. Buser, F. Borlat, S. Alouani, D. Soler, R. E. Offord, J.-M. Schroder, C. A. Power, and T. N. C. Wells (1999)
J. Biol. Chem. 274, 32478-32485
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The Mode and Duration of Anti-CD28 Costimulation Determine Resistance to Infection by Macrophage-Tropic Strains of Human Immunodeficiency Virus Type 1 In Vitro.
J. R. Creson, A. A. Lin, Q. Li, D. F. Broad, M. R. Roberts, and S. J. Anderson (1999)
J. Virol. 73, 9337-9347
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TNF-{alpha} Inhibits HIV-1 Replication in Peripheral Blood Monocytes and Alveolar Macrophages by Inducing the Production of RANTES and Decreasing C-C Chemokine Receptor 5 (CCR5) Expression.
B. R. Lane, D. M. Markovitz, N. L. Woodford, R. Rochford, R. M. Strieter, and M. J. Coffey (1999)
J. Immunol. 163, 3653-3661
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Characterization of RANTES- and Aminooxypentane-RANTES- Triggered Desensitization Signals Reveals Differences in Recruitment of the G Protein-Coupled Receptor Complex.
A. J. Vila-Coro, M. Mellado, A. Martin de Ana, C. Martinez-A., and J. M. Rodriguez-Frade (1999)
J. Immunol. 163, 3037-3044
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