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Targeting a host receptor instead of the virus: a new experimental approach against hepatitis C virus.

An international collaboration led by Professor Thomas Baumert (Inserm/University of Strasbourg Joint Research Unit 1110, “Institute for Viral and Liver Disease”) has shown that a monoclonal antibody directed specifically against claudin-1, a liver protein essential for infection by the hepatitis C virus (HCV), enables the prevention and treatment of chronic infection by this virus in an animal model. It turns out that this antibody, which was known to inhibit HCV entry and thereby prevent the initiation of infection, can also eliminate infected cells. This discovery, published in a letter in the Nature Biotechnology issue of 23 March 2015, opens the way to developing an approach to hepatitis C that is not only preventive, but therapeutic as well.

Infection with hepatitis C virus (HCV) leads to cirrhosis of the liver and liver cancer, the second leading cause of cancer death in the world. These complications are major indications for liver transplantation, but HCV reinfection of the transplant is a challenge. To date there is no vaccine, and the new treatments developed recently can be accessed by only a minority of patients worldwide because of their high cost. The development of new preventive and therapeutic strategies therefore continues.

The team directed by Prof. Thomas Baumert (Inserm/University of Strasbourg Joint Research Unit 1110, “Institute for Viral and Liver Disease”), in collaboration with international teams, decided to target a liver protein essential for viral infection instead of targeting the virus. They chose claudin-1, a molecule that is important in the initial steps of HCV infection, and involved in cell-cell contacts.

Using mouse models with humanised liver, the researchers show that a monoclonal antibody directed against claudin-1 can prevent HCV infection by blocking the entry of the virus into liver cells. Surprisingly, the researchers also observed that this antibody enables the treatment of chronic HCV infection by inhibiting the activation of intracellular signalling pathways needed by the virus for survival. As a result, the infected cells disappear and are gradually replaced by uninfected cells.

The advantage of this strategy is that it does not need to be combined with an antiviral agent.

 Moreover, by using different viral strains, the researchers show that it is difficult for the virus to escape from this antibody and develop resistance.

“Claudin-1” is a protein that is usually localised in the tight junctions that are the points of contact between adjacent cells. It is interesting to note that tight junction proteins constitute receptors for other pathogens, such as dengue virus and Shigella species. This innovative approach, employing injection of a monoclonal antibody directed against a protein on the host cell, makes it possible to foresee the development of a vaccine strategy and new therapeutic approaches against HCV, and also against other pathogens that use similar infection mechanisms.

This study received support from the European Union (ERC, INTERREG-IV-Upper Rhine [ERDF], FP7), ANRS (French National Agency for Research on AIDS and Viral Hepatitis), the HepSYS and netRNA Laboratories of Excellence of the French National Research Agency (ANR), ARC Foundation for Cancer Research, IHU Strasbourg MIX-Surg, Wilhelm Sander Foundation, Alsace Region, French National Cancer Institute (INCa), French National Institute of Health and Medical Research (Inserm), French National Scientific Research Centre (CNRS), University of Strasbourg, Ghent University (GOA 01G01712), Flanders Research Foundation (FWO) and Cardiex (Nantes).

Researcher Contact
Pr Thomas Baumert
Inserm UMR 1110, "Institut de recherche sur les maladies virales et hépatiques"
Tél : +33 (0)3 68 85 37 03
Mobile : +33 (0)6 11 58 23 87
Press Contact
Noella Lefebvre
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rf.srna@ervbefel.alleoN   Inserm
Juliette Hardy
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rf.mresni@esserp   Université de Strasbourg
Anne-Isabelle Bischoff
Tel. :+33 (0) 3 68 85 16 27
Mobile : +33 (0)6 47 58 72 05
Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody Laurent Mailly1, 2, Fei Xiao1, 2, *, Joachim Lupberger1, 2, *, Garrick K. Wilson3, Philippe Aubert4, 5, 6, François H. T. Duong7, Diego Calabrese7, Céline Leboeuf1, 2, Isabel Fofana1, 2, Christine Thumann1, 2, Simonetta Bandiera1, 2, Marc Lütgehetmann8, Tassilo Volz8, Christopher Davis3, Helen J. Harris3, Christopher J. Mee3, Erika Girardi2, 9, Béatrice Chane-Woon-Ming2, 9, Maria Ericsson10, Nicola Fletcher3, Ralf Bartenschlager11, 12, Patrick Pessaux1, 2, 13, Koen Vercauteren14, Philip Meuleman14, Pascal Villa2, 15, Lars Kaderali16, Sébastien Pfeffer2, 9, Markus H. Heim7, Michel Neunlist4, 5, 6, Mirjam B. Zeisel1, 2, Maura Dandri8, Jane A. McKeating3, Eric Robinet1, 2, § and Thomas F. Baumert1, 2, 13, §   1Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; 2Université de Strasbourg, Strasbourg, France; 3Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, United Kingdom; 4Institut National de la Santé et de la Recherche Médicale, U913, Nantes, France; 5Université de Nantes, Nantes, France; 6Institut des Maladies de l’Appareil Digestif, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, France; 7Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland; 8I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 9Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS – UPR 9002, Strasbourg, France; 10Electron Microscopy Facility, Harvard Medical School, Boston, USA; 11Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany; 12German Centre for Infection Research, Heidelberg University, Heidelberg, Germany; 13Pôle Hépato-Digestif, Institut Hospitalo-Universitaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; 14Center for Vaccinology, Ghent University, Ghent, Belgium; 15Plateforme de Chimie Biologique Intégrative de Strasbourg, UMS 3286 CNRS-UdS & FMTS, Illkirch, France; 16Institute for Medical Informatics and Biometry, Medical Faculty, Technische Universität Dresden, Dresden, Germany. *These authors contributed equally to the work.
  • These authors contributed equally to the work.
Nature Biotechnology, Advance Online Publication March 23, 2015 (LETTERS)