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1 MRC Virology Unit, Institute of Virology, University of Glasgow, Church Street, Glasgow G11 5JR, UK
2 Center for the Study of Hepatitis C, The Rockefeller University, New York, NY, USA
3 Twincore Center for Experimental and Clinical Infection Research, Department of Experimental Virology, Hannover, Germany
4 Helmholtz Center for Infection Research, Braunschweig, Germany
5 Medizinische Hochschule Hannover, Germany
6 Okairòs-Ceinge, Naples, Italy
7 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
Correspondence
Arvind H. Patel
a.patel{at}mrcvu.gla.ac.uk
Hepatitis C virus (HCV) infects cells by the direct uptake of cell-free virus following virus engagement with specific cell receptors such as CD81. Recent data have shown that HCV is also capable of direct cell-to-cell transmission, although the role of CD81 in this process is disputed. Here, we generated cell culture infectious strain JFH1 HCV (HCVcc) genomes carrying an alanine substitution of E2 residues W529 or D535 that are critical for binding to CD81 and infectivity. Co-cultivation of these cells with naïve cells expressing enhanced green fluorescent protein (EGFP) resulted in a small number of cells co-expressing both EGFP and HCV NS5A, showing that the HCVcc mutants are capable of cell-to-cell spread. In contrast, no cell-to-cell transmission from JFH1
E1E2-transfected cells occurred, indicating that the HCV glycoproteins are essential for this process. The frequency of cell-to-cell transmission of JFH1W529A was unaffected by the presence of neutralizing antibodies that inhibit E2–CD81 interactions. By using cell lines that expressed little or no CD81 and that were refractive to infection with cell-free virus, we showed that the occurrence of viral cell-to-cell transmission is not influenced by the levels of CD81 on either donor or recipient cells. Thus, our results show that CD81 plays no role in the cell-to-cell spread of HCVcc and that this mode of transmission is shielded from neutralizing antibodies. These data suggest that therapeutic interventions targeting the entry of cell-free HCV may not be sufficient in controlling an ongoing chronic infection, but need to be complemented by additional strategies aimed at disrupting direct cell-to-cell viral transmission.
Published online ahead of print on 3 October 2008 as DOI 10.1099/vir.0.2008/006700-0.
Supplementary material is available with the online version of this paper.
This article has been cited by other articles:
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  C. Brohm, E. Steinmann, M. Friesland, I. C. Lorenz, A. Patel, F. Penin, R. Bartenschlager, and T. Pietschmann Characterization of Determinants Important for Hepatitis C Virus p7 Function in Morphogenesis by Using trans-Complementation J. Virol., November 15, 2009; 83(22): 11682 - 11693. [Abstract] [Full Text] [PDF]
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Z.-y. Keck, S. H. Li, J. Xia, T. von Hahn, P. Balfe, J. A. McKeating, J. Witteveldt, A. H. Patel, H. Alter, C. M. Rice, et al. Mutations in Hepatitis C Virus E2 Located outside the CD81 Binding Sites Lead to Escape from Broadly Neutralizing Antibodies but Compromise Virus Infectivity J. Virol., June 15, 2009; 83(12): 6149 - 6160. [Abstract] [Full Text] [PDF]
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