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Antimicrobial Agents and Chemotherapy, April 2002, p. 982-990, Vol. 46, No. 4
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.4.982-990.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Hemofiltrate CC Chemokine 1[9-74] Causes Effective Internalization of CCR5 and Is a Potent Inhibitor of R5-Tropic Human Immunodeficiency Virus Type 1 Strains in Primary T Cells and Macrophages

Jan Münch,1,{dagger} Ludger Ständker,2 Stefan Pöhlmann,3 Frédéric Baribaud,3 Armin Papkalla,1 Olaf Rosorius,1 Roland Stauber,1 Gabriele Sass,4 Nikolaus Heveker,5 Knut Adermann,2 Sylvia Escher,2 Enno Klüver,2 Robert W. Doms,3 Wolf-Georg Forssmann,2 and Frank Kirchhoff1*

Institute for Clinical and Molecular Virology,1 Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, 91054 Erlangen,4 IPF PharmaCeuticals GmbH, 30625 Hannover, Germany,2 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 ,3 Institute Cochin de Genetique Moleculaire, INSERM, 75014 Paris, France5

Received 13 August 2001/ Returned for modification 6 November 2001/ Accepted 27 December 2001

Proteolytic processing of the abundant plasmatic human CC chemokine 1 (HCC-1) generates a truncated form, HCC-1[9-74], which is a potent agonist of CCR1, CCR3, and CCR5; promotes calcium influx and chemotaxis of T lymphoblasts, monocytes, and eosinophils; and inhibits infection by CCR5-tropic human immunodeficiency virus type 1 (HIV-1) isolates. In the present study we demonstrate that HCC-1[9-74] interacts with the second external loop of CCR5 and inhibits replication of CCR5-tropic HIV-1 strains in both primary T cells and monocyte-derived macrophages. Low concentrations of the chemokine, however, frequently enhanced the replication of CCR5-tropic HIV-1 isolates but not the replication of X4-tropic HIV-1 isolates. Only HCC-1[9-74] and HCC-1[10-74], but not other HCC-1 length variants, displayed potent anti-HIV-1 activities. Fluorescence-activated cell sorter analysis revealed that HCC-1[9-74] caused up to 75% down-regulation of CCR5 cell surface expression, whereas RANTES (regulated on activation, normal T-cell expressed and secreted) achieved a reduction of only about 40%. Studies performed with green fluorescent protein-tagged CCR5 confirmed that both HCC-1[9-74] and RANTES, but not full-length HCC-1, mediated specific internalization of the CCR5 HIV-1 entry cofactor. Our results demonstrate that the interaction with HCC-1[9-74] causes effective intracellular sequestration of CCR5, but they also indicate that the effect of HCC-1[9-74] on viral replication is subject to marked cell donor- and HIV-1 isolate-dependent variations.

* Corresponding author. Present address: Abteilung Virologie-Universitätsklinikum, Albert-Einstein-Allee 11, 89081 Ulm, Germany. Phone: 49-731-50023344. Fax: 49-731-50023389. E-mail: frank.kirchhoff{at}medizin.uni-ulm.de.

{dagger} Present address: Abteilung Virologie-Universitätsklinikum, 89081 Ulm, Germany.

Antimicrobial Agents and Chemotherapy, April 2002, p. 982-990, Vol. 46, No. 4
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.4.982-990.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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