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J. Biol. Chem., Vol. 280, Issue 9, 7793-7799, March 4, 2005
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From the CNRS-UPR2511, Institut de Biologie de Lille and Institut Pasteur de Lille, Lille 59021, France
The scavenger receptor class B type I (SR-BI) has recently been shown to interact with hepatitis C virus (HCV) envelope glycoprotein E2, suggesting that it might be involved at some step of HCV entry into host cells. However, due to the absence of a cell culture system to efficiently amplify HCV, it is not clear how SR-BI contributes to HCV entry. Here, we sought to determine how high density lipoproteins (HDLs), the natural ligand of SR-BI, affect HCV entry. By using the recently described infectious HCV pseudotyped particles (HCVpps) that display functional E1E2 glycoprotein complexes, we showed that HDLs are able to markedly enhance HCVpp entry. We did not find any evidence of HDL association with HCVpps, suggesting that HCVpps do not enter into target cells using HDL as a carrier to bind to its receptor. Interestingly, lipid-free apoA-I and apoA-II, the major HDL apolipoproteins, were unable to enhance HCVpp infectivity. In addition, drugs inhibiting HDL cholesteryl transfer (block lipid transport (BLT)-2 and BLT-4) reduced HDL enhancement of HCVpp entry, suggesting a role for lipid transfer in facilitating HCVpp entry. Importantly, silencing of SR-BI expression in target cells by RNA interference markedly reduced HDL-mediated enhancement of HCVpp entry. Finally, enhancement of HCVpp entry was also suppressed when the SR-BI binding region on HCV glycoprotein E2 was deleted. Altogether, these data indicate that HDL-mediated enhancement of HCVpp entry involves a complex interplay between SR-BI, HDL, and HCV envelope glycoproteins, and they highlight the active role of HDLs in HCV entry.
Received for publication, October 12, 2004 , and in revised form, December 14, 2004.
* This work was supported by grants from INSERM (ATC "hépatite C") and the Agence Nationale de Recherche sur le Sida et les Hépatites Virales and European Union Grants QLRT-2000-01120 and QLRT-2001-0132. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Supported by a CNRS post-doctoral fellowship.
Supported by an Agence Nationale de Recherche sur le Sida et les Hépatites Virales post-doctoral fellowship.
¶ Contributed equally to this study.
|| To whom correspondence should be addressed: Unité Hépatite C, CNRS-UPR2511, Institut de Biologie de Lille, 1 rue Calmette, BP447, 59021 Lille cedex, France. Tel.: 33-3-20-87-11-60; Fax: 33-3-20-87-12-01; E-mail: jean.dubuisson{at}ibl.fr.
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