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Journal of Virology, January 2007, p. 588-598, Vol. 81, No. 2
0022-538X/07/$08.00+0     doi:10.1128/JVI.01534-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Level of CD81 Cell Surface Expression Is a Key Determinant for Productive Entry of Hepatitis C Virus into Host Cells{triangledown}

George Koutsoudakis,1 Eva Herrmann,2 Stephanie Kallis,1 Ralf Bartenschlager,1* and Thomas Pietschmann1

Department Molecular Virology, University Heidelberg, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany,1 Department of Internal Medicine, Faculty of Medicine, Saarland University, Kirrberger Strasse, 66421 Homburg Saar, Germany2

Received 18 July 2006/ Accepted 22 October 2006

Recently a cell culture model supporting the complete life cycle of the hepatitis C virus (HCV) was developed. Searching for host cell determinants involved in the HCV replication cycle, we evaluated the efficiency of virus propagation in different Huh-7-derived cell clones. We found that Huh-7.5 cells and Huh7-Lunet cells, two former replicon cell clones that had been generated by removal of an HCV replicon by inhibitor treatment, supported comparable levels of RNA replication and particle production, whereas virus spread was severely impaired in the latter cells. Analysis of cell surface expression of CD81 and scavenger receptor class B type I (SR-BI), two molecules previously implicated in HCV entry, revealed similar expression levels for SR-BI, while CD81 surface expression was much higher on Huh-7.5 cells than on Huh7-Lunet cells. Ectopic expression of CD81 in Huh7-Lunet cells conferred permissiveness for HCV infection to a level comparable to that for Huh-7.5 cells. Modulation of CD81 cell surface density in Huh-7.5 cells by RNA interference indicated that a certain amount of this molecule (~7 x 104 molecules per cell) is required for productive infection with a low dose of HCV. Consistent with this, we show that susceptibility to HCV infection depends on a critical quantity of CD81 molecules. While infection is restricted in cells expressing very small amounts of CD81, susceptibility rapidly rises within a narrow range of CD81 levels, reaching a plateau where higher expression does not further increase the efficiency of infection. Together these data indicate that a high density of cell surface-exposed CD81 is a key determinant for productive HCV entry into host cells.

* Corresponding author. Mailing address: Department Molecular Virology, University Heidelberg, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany. Phone: 49 6221 564569. Fax: 49 6221 564570. E-mail: ralf_bartenschlager{at}med.uni-heidelberg.de.

{triangledown} Published ahead of print on 1 November 2006.

Journal of Virology, January 2007, p. 588-598, Vol. 81, No. 2
0022-538X/07/$08.00+0     doi:10.1128/JVI.01534-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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