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Viruses 2018, 10(4), 207; https://doi.org/10.3390/v10040207

CD81 Receptor Regions outside the Large Extracellular Loop Determine Hepatitis C Virus Entry into Hepatoma Cells

1
Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, 30625 Hannover, Germany
2
Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA
Current address: Tri-Institutional Therapeutics Discovery Institute (Tri-I TDI) Weill Cornell Medicine, New York, NY 10021, USA.
Current address: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-9806, USA.
*
Author to whom correspondence should be addressed.
Received: 18 March 2018 / Revised: 14 April 2018 / Accepted: 19 April 2018 / Published: 20 April 2018
(This article belongs to the Section Animal Viruses)
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Abstract

Hepatitis C virus (HCV) enters human hepatocytes using four essential entry factors, one of which is human CD81 (hCD81). The tetraspanin hCD81 contains a large extracellular loop (LEL), which interacts with the E2 glycoprotein of HCV. The role of the non-LEL regions of hCD81 (intracellular tails, four transmembrane domains, small extracellular loop and intracellular loop) is poorly understood. Here, we studied the contribution of these domains to HCV susceptibility of hepatoma cells by generating chimeras of related tetraspanins with the hCD81 LEL. Our results show that non-LEL regions in addition to the LEL determine susceptibility of cells to HCV. While closely related tetraspanins (X. tropicalis CD81 and D. rerio CD81) functionally complement hCD81 non-LEL regions, distantly related tetraspanins (C. elegans TSP9 amd D. melanogaster TSP96F) do not and tetraspanins with intermediate homology (hCD9) show an intermediate phenotype. Tetraspanin homology and susceptibility to HCV correlate positively. For some chimeras, infectivity correlates with surface expression. In contrast, the hCD9 chimera is fully surface expressed, binds HCV E2 glycoprotein but is impaired in HCV receptor function. We demonstrate that a cholesterol-coordinating glutamate residue in CD81, which hCD9 lacks, promotes HCV infection. This work highlights the hCD81 non-LEL regions as additional HCV susceptibility-determining factors. View Full-Text
Keywords: hepatitis C virus; HCV; tetraspanin; CD81; receptor; chimeras; susceptibility-determining domains; transmembrane domain four; cholesterol-binding residue hepatitis C virus; HCV; tetraspanin; CD81; receptor; chimeras; susceptibility-determining domains; transmembrane domain four; cholesterol-binding residue
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Banse, P.; Moeller, R.; Bruening, J.; Lasswitz, L.; Kahl, S.; Khan, A.G.; Marcotrigiano, J.; Pietschmann, T.; Gerold, G. CD81 Receptor Regions outside the Large Extracellular Loop Determine Hepatitis C Virus Entry into Hepatoma Cells. Viruses 2018, 10, 207.

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