Document Detail


EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy.
MedLine Citation:
PMID:  21516087     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Hepatitis C virus (HCV) is a major cause of liver disease, but therapeutic options are limited and there are no prevention strategies. Viral entry is the first step of infection and requires the cooperative interaction of several host cell factors. Using a functional RNAi kinase screen, we identified epidermal growth factor receptor and ephrin receptor A2 as host cofactors for HCV entry. Blocking receptor kinase activity by approved inhibitors broadly impaired infection by all major HCV genotypes and viral escape variants in cell culture and in a human liver chimeric mouse model in vivo. The identified receptor tyrosine kinases (RTKs) mediate HCV entry by regulating CD81-claudin-1 co-receptor associations and viral glycoprotein-dependent membrane fusion. These results identify RTKs as previously unknown HCV entry cofactors and show that tyrosine kinase inhibitors have substantial antiviral activity. Inhibition of RTK function may constitute a new approach for prevention and treatment of HCV infection.
Authors:
Joachim Lupberger; Mirjam B Zeisel; Fei Xiao; Christine Thumann; Isabel Fofana; Laetitia Zona; Christopher Davis; Christopher J Mee; Marine Turek; Sebastian Gorke; Cathy Royer; Benoit Fischer; Muhammad N Zahid; Dimitri Lavillette; Judith Fresquet; François-Loïc Cosset; S Michael Rothenberg; Thomas Pietschmann; Arvind H Patel; Patrick Pessaux; Michel Doffoël; Wolfgang Raffelsberger; Olivier Poch; Jane A McKeating; Laurent Brino; Thomas F Baumert
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-04-24
Journal Detail:
Title:  Nature medicine     Volume:  17     ISSN:  1546-170X     ISO Abbreviation:  Nat. Med.     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-05-06     Completed Date:  2011-07-05     Revised Date:  2014-03-12    
Medline Journal Info:
Nlm Unique ID:  9502015     Medline TA:  Nat Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  589-95     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD / physiology
Antigens, CD81
Antiviral Agents / pharmacology
Base Sequence
Cell Line
Claudin-1
Hepacivirus / drug effects,  physiology*
Hepatitis C / physiopathology*,  prevention & control,  therapy,  virology*
Host-Pathogen Interactions / physiology
Humans
Ligands
Membrane Proteins / physiology
Mice
Protein Kinase Inhibitors / pharmacology
Quinazolines / pharmacology
RNA Interference
RNA, Small Interfering / genetics
Receptor, EphA2 / antagonists & inhibitors,  genetics,  physiology*
Receptor, Epidermal Growth Factor / antagonists & inhibitors,  genetics,  physiology*
Virus Internalization* / drug effects
Grant Support
ID/Acronym/Agency:
1K08DE020139-01A1/DE/NIDCR NIH HHS; G0400802//Medical Research Council; G0801976//Medical Research Council; MC_U130184144//Medical Research Council; //Howard Hughes Medical Institute; //Medical Research Council; //Wellcome Trust
Chemical
Reg. No./Substance:
0/Antigens, CD; 0/Antigens, CD81; 0/Antiviral Agents; 0/CD81 protein, human; 0/CLDN1 protein, human; 0/Cd81 protein, mouse; 0/Claudin-1; 0/Cldn1 protein, mouse; 0/Ligands; 0/Membrane Proteins; 0/Protein Kinase Inhibitors; 0/Quinazolines; 0/RNA, Small Interfering; EC 2.7.10.1/Receptor, EphA2; EC 2.7.10.1/Receptor, Epidermal Growth Factor; J4T82NDH7E/erlotinib
Comments/Corrections
Comment In:
Nat Rev Gastroenterol Hepatol. 2011 Jul;8(7):361   [PMID:  21725346 ]
J Hepatol. 2012 Jan;56(1):282-4   [PMID:  21784050 ]
Hepatology. 2011 Oct;54(4):1472-5   [PMID:  21956707 ]
Nat Med. 2011 May;17(5):542-4   [PMID:  21546968 ]

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