Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antigens, CD / physiology
-
Antiviral Agents / pharmacology
-
Base Sequence
-
Cell Line
-
Claudin-1
-
ErbB Receptors / antagonists & inhibitors
-
ErbB Receptors / genetics
-
ErbB Receptors / physiology*
-
Erlotinib Hydrochloride
-
Hepacivirus / drug effects
-
Hepacivirus / physiology*
-
Hepatitis C / physiopathology*
-
Hepatitis C / prevention & control
-
Hepatitis C / therapy
-
Hepatitis C / 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
-
Receptor, EphA2 / genetics
-
Receptor, EphA2 / physiology*
-
Tetraspanin 28
-
Virus Internalization* / drug effects
Substances
-
Antigens, CD
-
Antiviral Agents
-
CD81 protein, human
-
CLDN1 protein, human
-
Cd81 protein, mouse
-
Claudin-1
-
Cldn1 protein, mouse
-
Ligands
-
Membrane Proteins
-
Protein Kinase Inhibitors
-
Quinazolines
-
RNA, Small Interfering
-
Tetraspanin 28
-
Erlotinib Hydrochloride
-
ErbB Receptors
-
Receptor, EphA2