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Journal of Virology, March 2002, p. 2245-2254, Vol. 76, No. 5
0022-538X/02/$04.00+0     DOI: 10.1128/jvi.76.5.2245-2254.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Interaction of the CC-Chemokine RANTES with Glycosaminoglycans Activates a p44/p42 Mitogen-Activated Protein Kinase-Dependent Signaling Pathway and Enhances Human Immunodeficiency Virus Type 1 Infectivity

*** Theresa Li-Yun Chang,1 Cynthia J. Gordon,2,{dagger} Branka Roscic-Mrkic,3 Christine Power,4 Amanda E. I. Proudfoot,4 John P. Moore,1 and Alexandra Trkola3*

Department of Microbiology and Immunology, Weill Medical College of Cornell University,,1 Department of Pathology, New York University School of Medicine, New York, New York,2 Division of Infectious Diseases, Department of Medicine, University Hospital Zurich, Zurich,3 Serono Pharmaceutical Research Institute, 1228 Plan-Les-Ouates, Geneva, Switzerland4

Received 1 August 2001/ Accepted 27 November 2001

The interaction of the CC-chemokine RANTES with its cell surface receptors transduces multiple intracellular signals: low concentrations of RANTES (1 to 10 nM) stimulate G-protein-coupled receptor (GPCR) activity, and higher concentrations (1 µM) activate a phosphotyrosine kinase (PTK)-dependent pathway. Here, we show that the higher RANTES concentrations induce rapid tyrosine phosphorylation of multiple proteins. Several src-family kinases (Fyn, Hck, Src) are activated, as is the focal adhesion kinase p125 FAK and, eventually, members of the p44/p42 mitogen-activated protein kinase (MAPK) family. This PTK signaling pathway can be activated independently of known seven-transmembrane GPCRs for RANTES because it occurs in cells that lack any such RANTES receptors. Instead, activation of the PTK signaling pathway is dependent on the expression of glycosaminoglycans (GAGs) on the cell surface, in that it could not be activated by RANTES in GAG-deficient cells. We have previously demonstrated that RANTES can both enhance and inhibit infection of cells with human immunodeficiency virus type 1 (HIV-1). Here we show that activation of both PTK and MAPK is involved in the enhancement of HIV-1 infectivity caused by RANTES in cells that lack GPCRs for RANTES but which express GAGs.

* Corresponding author. Mailing address: Division of Infectious Diseases, Department of Medicine, University Hospital Zurich, Ramistrasse 100 E RAE 3, 8091 Zurich, Switzerland. Phone: 41-1-255-5976. Fax: 41-1-255-3291. E-mail: alexandra.trkola{at}DIM.usz.ch.

{dagger} Present address: CNS News, New York, NY 10036.

Journal of Virology, March 2002, p. 2245-2254, Vol. 76, No. 5
0022-538X/02/$04.00+0     DOI: 10.1128/jvi.76.5.2245-2254.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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