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

Joachim Lupberger et al.  Nature Medicine (2011)17:589–595

Speaker: Szu-Han Kuo (郭思含)                                  Time:11/16/2011, 15:00-16:00

Commentator: Dr. Kung-Chia Young (楊孔嘉老師)    Location: Room 601

Abstract

Hepatitis C virus (HCV) also called non-A non-B hepatitis (NANB) virus is a major cause of liver diseases. It has been a challenging pathogen for researchers and clinicians, because the therapeutic options are limited and there are no prevention strategies¹. Viral entry is the first step of infection and requires the cooperative interaction of several host cell factors. Using a functional RNAi kinase screening, the authors identified the epidermal growth factor receptor (EGFR) and ephrin receptor A2 (EphA2) as the host cofactors for HCV entry. Furthermore, EGFR and EphA2 are highly expressed in human liver and their kinase function can be inhibited by clinically approved protein kinase inhibitors (PKIs, such as Erlotinib, which is used for lung cancer treatment²). These molecules were further explored to clarify whether they can be used as therapeutic targets. In this paper, the authors identified EGFR and EphA2 as the co-factor for HCV entry by PKIs and monoclonal RTK-specific antibody. They further revealed that RTK not only promote CD81-Claudin-1 (HCV receptors) association and viral glycoprotein-dependent membrane fusion but also play a role in cell-to-cell transmission and viral spread³. Furthermore, the authors blocked the receptor kinase activity by FDA (U.S. Food and Drug Administration) approved PKIs, which broadly impair the infection by all of the major HCV genotypes and viral escape variants in cell culture and in achimeric mouse model. They also identified a RTK-specific mAb that inhibits viral entry. In conclusion, RTK is identified as a novel co-factor for HCV entry, inhibition of RTK function by using small molecules or antibodies may sustain the antiviral activity and contribute a new approach for prevention and treatment of HCV infection.

References

1.         Timpe, J.M. & McKeating, J.A. Hepatitis C virus entry: possible targets for therapy. Gut 57, 1728-1737 (2008).

2.         Frances A. Shepherd, M.D., José Rodrigues Pereira, M.D., Tudor Ciuleanu, M.D., Eng Huat Tan, M.D.,, et al. Erlotinib in Previously Treated Non–Small-Cell Lung Cancer. The New England Journal of Medicine 353, 123-132 (2005).

3.         Evans, M.J., et al. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature 446, 801-805 (2007).