Viral entry and escape from antibody-mediated neutralization influence hepatitis C virus reinfection in liver transplantation

Published August 16, 2010
The Rockefeller University Press, doi: 10.1084/jem.20090766
© 2010 Fafi-Kremer et al.

Article

Samira Fafi-Kremer 1,2,3, Isabel Fofana 1,2, Eric Soulier 1,2, Patric Carolla 1,2, Philip Meuleman 6, Geert Leroux-Roels 6, Arvind H. Patel 7, François-Loïc Cosset 8, Patrick Pessaux 2,4, Michel Doffoël 1,2,5, Philippe Wolf 1,2,4, Françoise Stoll-Keller 1,2,3, and Thomas F. Baumert 1,2,3,5

+ Author Affiliations

1 Institut National de la Santé et de la Recherche Médicale, Unité 748, F-67000 Strasbourg, France
2 Université de Strasbourg, F-67000 Strasbourg, France
3 Laboratoire de Virologie,
4 Pôle des Pathologies Digestives, Hépatiques et Transplantation, and
5 Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, F-67000 Strasbourg, France
6 Center for Vaccinology, Ghent University and Hospital, 9000 Ghent, Belgium
7 Medical Research Council Centre for Virus Research, University of Glasgow, Glasgow G11 5JR, Scotland, UK

8Institut National de la Santé et de la Recherche Médicale, Unité 758, Institut Fédératif de Recherche 128, Ecole Normale Supérieure, Université Claude Bernard Lyon 1, Université de Lyon, F-69007 Lyon, France

CORRESPONDENCE Thomas F. Baumert: Thomas.Baumert@unistra.fr OR Françoise Stoll-Keller: francoise.stoll@unistra.fr

Abstract

End-stage liver disease caused by chronic hepatitis C virus (HCV) infection is a leading cause for liver transplantation (LT). Due to viral evasion from host immune responses and the absence of preventive antiviral strategies, reinfection of the graft is universal. The mechanisms by which the virus evades host immunity to reinfect the liver graft are unknown. In a longitudinal analysis of six HCV-infected patients undergoing LT, we demonstrate that HCV variants reinfecting the liver graft were characterized by efficient entry and poor neutralization by antibodies present in pretransplant serum compared with variants not detected after transplantation. Monoclonal antibodies directed against HCV envelope glycoproteins or a cellular entry factor efficiently cross-neutralized infection of human hepatocytes by patient-derived viral isolates that were resistant to autologous host-neutralizing responses. These findings provide significant insights into the molecular mechanisms of viral evasion during HCV reinfection and suggest that viral entry is a viable target for prevention of HCV reinfection of the liver graft.

Footnotes

Abbreviations used:

ANOV Aanalysis of variance
HCV hepatitis C virus
HCVpp HCV pseudoparticle
LT liver transplantationu
PA-SCID urokinase-type plasminogen activator/severe combined immunodeficient

Submitted: 7 April 2009
Accepted: 8 July 2010

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