EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy

Area of Science:

• Hepatology
• Virology
• Molecular Biology

Background:

• Hepatitis C virus (HCV) infection is a significant global health issue causing liver disease.
• Current therapeutic options for HCV are limited, and effective prevention strategies are lacking.
• HCV viral entry is a critical step in infection, dependent on host cell factors.

Purpose of the Study:

• To identify host cell factors essential for HCV entry.
• To evaluate the antiviral potential of targeting these identified factors.

Main Methods:

• A functional RNA interference (RNAi) kinase screen was employed to identify host cofactors.
• Approved tyrosine kinase inhibitors were used to block identified receptor kinase activity.
• HCV infection was assessed in cell culture and a human liver chimeric mouse model in vivo.

Main Results:

• Epidermal growth factor receptor (EGFR) and ephrin receptor A2 (EphA2) were identified as host cofactors for HCV entry.
• Inhibition of EGFR and EphA2 kinase activity broadly impaired infection across major HCV genotypes and escape variants.
• Receptor tyrosine kinases (RTKs) were shown to regulate CD81-claudin-1 co-receptor associations and viral fusion.

Conclusions:

• Receptor tyrosine kinases (RTKs) are previously unrecognized cofactors for HCV entry.
• Approved tyrosine kinase inhibitors demonstrate significant antiviral activity against HCV.
• Targeting RTK function presents a novel therapeutic and preventative strategy for HCV infection.