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Journal of Virology, August 2004, p. 8322-8332, Vol. 78, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.15.8322-8332.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus Targets DC-SIGN and L-SIGN To Escape Lysosomal Degradation

Irene S. Ludwig,1 Annemarie N. Lekkerkerker,1 Erik Depla,2 Fons Bosman,2 René J. P. Musters,3 Stany Depraetere,2 Yvette van Kooyk,1 and Teunis B. H. Geijtenbeek1*

Department of Molecular Cell Biology and Immunology,1 Laboratory of Physiology, Vrije Universiteit Medical Center Amsterdam, 1081 BT Amsterdam, The Netherlands,3 Innogenetics N.V., B-9025 Ghent, Belgium2

Received 19 November 2003/ Accepted 29 March 2004

Hepatitis C virus (HCV) is a major health problem. However, the mechanism of hepatocyte infection is largely unknown. We demonstrate that the dendritic cell (DC)-specific C-type lectin DC-SIGN and its liver-expressed homologue L-SIGN/DC-SIGNR are important receptors for HCV envelope glycoproteins E1 and E2. Mutagenesis analyses demonstrated that both HCV E1 and E2 bind the same binding site on DC-SIGN as the pathogens human immunodeficiency virus type 1 (HIV-1) and mycobacteria, which is distinct from the cellular ligand ICAM-3. HCV virus-like particles are efficiently captured and internalized by DCs through binding of DC-SIGN. Antibodies against DC-SIGN specifically block HCV capture by both immature and mature DCs, demonstrating that DC-SIGN is the major receptor on DCs. Interestingly, internalized HCV virus-like particles were targeted to nonlysosomal compartments within immature DCs, where they are protected from lysosomal degradation in a manner similar to that demonstrated for HIV-1. Lewis X antigen, another ligand of DC-SIGN, was internalized to lysosomes, demonstrating that the internalization pathway of DC-SIGN-captured ligands may depend on the structure of the ligand. Our results suggest that HCV may target DC-SIGN to "hide" within DCs and facilitate viral dissemination. L-SIGN, expressed by THP-1 cells, internalized HCV particles into similar nonlysosomal compartments, suggesting that L-SIGN on liver sinusoidal endothelial cells may capture HCV from blood and transmit it to hepatocytes, the primary target for HCV. We therefore conclude that both DCs and liver sinusoidal endothelial cells may act as reservoirs for HCV and that the C-type lectins DC-SIGN and L-SIGN, as important HCV receptors, may represent a molecular target for clinical intervention in HCV infection.

* Corresponding author. Mailing address: Department of Molecular Cell Biology and Immunology, Free University Medical Center Amsterdam, v.d. Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. Phone: (31)20-4448080. Fax: (31)20-4448081. E-mail: T.Geijtenbeek{at}vumc.nl.

Journal of Virology, August 2004, p. 8322-8332, Vol. 78, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.15.8322-8332.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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