期刊
NATURE MEDICINE
卷 17, 期 5, 页码 589-U109出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2341
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资金
- European Research Council [ERC-2008-AdG-233130-HEPCENT]
- INTERREG-IV-Rhin Superieur-FEDER-Hepato-Regio-Net
- Agence Nationale de la Recherche [ANR-05-CEXC-008]
- Agence Nationale de Recherche sur le Sida [2008/354]
- Region Alsace
- Institut National du Cancer
- Institut de Genetique et de Biologie Moleculaire et Cellulaire
- Institut National de la Sante et de la Recherche Medicale
- Centre National de la Recherche Scientifique
- Universite de Strasbourg
- US National Insititutes of Health [1K08DE020139-01A1]
- UK Medical Research Council
- Wellcome Trust
- MRC [G0400802, MC_U130184144, G0801976] Funding Source: UKRI
- Medical Research Council [G0400802, G0801976, MC_U130184144] Funding Source: researchfish
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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