EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy
Joachim Lupberger,Mirjam B. Zeisel,Mirjam B. Zeisel,Fei Xiao,Fei Xiao,Christine Thumann,Christine Thumann,Isabel Fofana,Isabel Fofana,Laetitia Zona,Laetitia Zona,Christopher Davis,Christopher J. Mee,Marine Turek,Marine Turek,Sebastian Gorke,Cathy Royer,Cathy Royer,Benoit Fischer,Muhammad N. Zahid,Muhammad N. Zahid,Dimitri Lavillette,Judith Fresquet,François-Loïc Cosset,S. Michael Rothenberg,Thomas Pietschmann,Arvind H. Patel,Patrick Pessaux,Michel Doffoel,Wolfgang Raffelsberger,Olivier Poch,Jane A. McKeating,Laurent Brino,Thomas F. Baumert,Thomas F. Baumert +34 more
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Inhibition of RTK function may constitute a new approach for prevention and treatment of HCV infection and show that tyrosine kinase inhibitors have substantial antiviral activity.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.read more
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Understanding the hepatitis C virus life cycle paves the way for highly effective therapies
TL;DR: Ongoing and future trials will determine the best antiviral combinations and whether the current seemingly rich pipeline is sufficient for successful treatment of all patients in the face of major challenges, such as HCV diversity, viral resistance, the influence of host genetics, advanced liver disease and other co-morbidities.
Journal ArticleDOI
Living in the liver: hepatic infections
TL;DR: The interplay between pathogens and host factors that promote pathogen elimination and maintain organ integrity or that allow pathogen persistence are described.
Journal ArticleDOI
Identification of the Niemann-Pick C1–like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor
Bruno Sainz,Naina Barretto,Danyelle N. Martin,Nobuhiko Hiraga,Michio Imamura,Snawar Hussain,Katherine A. Marsh,Xuemei Yu,Kazuaki Chayama,Waddah A. Alrefai,Susan L. Uprichard +10 more
TL;DR: It is shown that the cellular Niemann-Pick C1–like 1 (NPC1L1) cholesterol uptake receptor is an HCV entry factor amendable to therapeutic intervention and discovered a new antiviral target and potential therapeutic agent.
Journal ArticleDOI
Current and future therapies for hepatitis C virus infection.
T. Jake Liang,Marc G. Ghany +1 more
TL;DR: As therapy improves, systemwide identification and care of patients who need treatment will be the next challenge.
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The cell biology of receptor-mediated virus entry.
Joe Grove,Mark Marsh +1 more
TL;DR: The cell imposes multiple barriers to virus entry, but viruses exploit fundamental cellular processes to gain entry to cells and deliver their genetic cargo.
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