| EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. | |
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MedLine Citation:
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PMID: 21516087 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-04-24 |
Journal Detail:
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Title: Nature medicine Volume: 17 ISSN: 1546-170X ISO Abbreviation: Nat. Med. Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-05-06 Completed Date: 2011-07-05 Revised Date: 2012-01-25 |
Medline Journal Info:
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Nlm Unique ID: 9502015 Medline TA: Nat Med Country: United States |
Other Details:
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Languages: eng Pagination: 589-95 Citation Subset: IM |
Affiliation:
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Institut National de la Santé et de la Recherche Médicale, U748, Strasbourg, France. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antigens, CD / physiology Antigens, CD81 Antiviral Agents / pharmacology Base Sequence Cell Line 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:
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1K08DE020139-01A1/DE/NIDCR NIH HHS; //Howard Hughes Medical Institute; //Medical Research Council; //Wellcome Trust |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD; 0/Antigens, CD81; 0/Antiviral Agents; 0/CD81 protein, human; 0/Cd81 protein, mouse; 0/Ligands; 0/Membrane Proteins; 0/Protein Kinase Inhibitors; 0/Quinazolines; 0/RNA, Small Interfering; 0/claudin 1; 0/erlotinib; EC 2.7.10.1/Receptor, EphA2; EC 2.7.10.1/Receptor, Epidermal Growth Factor |
| Comments/Corrections | |
Comment In:
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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 ] |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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