Natural Proteolytic Processing of Hemofiltrate CC Chemokine 1 Generates a Potent CC Chemokine Receptor (CCR)1 and CCR5 Agonist with Anti-HIV Properties

doi:10.1084/jem.192.10.1501

Published online 20 November 2000.

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© The Rockefeller University Press, 0022-1007/2000/11/1501/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 10, November 20, 2000 1501-1508

Original Article

Natural Proteolytic Processing of Hemofiltrate CC Chemokine 1 Generates a Potent CC Chemokine Receptor (CCR)1 and CCR5 Agonist with Anti-HIV Properties

Michel Detheux^a, Ludger Ständker^b, Jalal Vakili^c, Jan Münch^d, Ulf Forssmann^b,e, Knut Adermann^b, Stefan Pöhlmann^d, Gilbert Vassart^c, Frank Kirchhoff^d, Marc Parmentier^c, and Wolf-Georg Forssmann^b
^a From Euroscreen S.A., B-1070 Brussels, Belgium
^b The Lower Saxony Institute for Peptide Research (IPF), D-30625 Hannover, Germany
^c Institute of Interdisciplinary Research, Université Libre de Bruxelles, B-1070 Brussels, Belgium
^d Institute for Clinical and Molecular Virology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany
^e Department of Urology, Johannes Gutenberg University, 55131 Mainz, Germany

Correspondence to: Marc Parmentier, IRIBHN, ULB, Campus Erasme, 808 Route de Lennik, B-1070 Bruxelles, Belgium. Tel:32-2-555-41-71 Fax:32-2-555-46-55

Hemofiltrate CC chemokine (HCC)-1 is a recently described humanchemokine that is constitutively expressed in numerous tissuesand is present at high concentrations in normal plasma. Usinga cell line expressing CC chemokine receptor (CCR)5 as a bioassay,we isolated from human hemofiltrate an HCC-1 variant lackingthe first eight amino acids. HCC-1[9–74] was a potentagonist of CCR1, CCR3, and CCR5 and promoted calcium flux andchemotaxis of T lymphoblasts, monocytes, and eosinophils. Italso blocked entry of HIV-1 strains using CCR5 as coreceptor.Limited tryptic digestion of HCC-1 generated the active variant.Conditioned media from several tumor cell lines activated HCC-1with a high efficiency, and this activity could be inhibitedby serine protease inhibitors. Our results indicate that HCC-1represents a nonfunctional precursor that can be rapidly convertedto the active chemokine by proteolytic processing. This processrepresents an additional mechanism by which tumor cells mightgenerate chemoattractant molecules and recruit inflammatorycells. It might also affect HIV-1 replication in infected individualsand play an important role in AIDS pathogenesis.

Key Words: receptors, CCR5, chemokines, CC, biological assay, endopeptidase,HIV

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