Current Topics in Microbiology and Immunology Ralf Bartenschlager Editor Hepatitis C Virus: From Molecular Virology to Antiviral Therapy Current Topics in Microbiology and Immunology Volume 369 Series Editors Klaus Aktories Medizinische Fakultät, Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Abt. I Albert- Ludwigs-Universität Freiburg, Albertstr. 25 79104 Freiburg, Germany Richard W. Compans Department of Microbiology and Immunology, Emory University, 1518 Clifton Road, CNR 5005, Atlanta, GA 30322, USA Max D. Cooper Department of Pathology and Laboratory Medicine, Georgia Research Alliance, Emory University, 1462 Clifton Road, Atlanta, GA 30322, USA Jorge E. Galan Boyer Ctr. for Molecular Medicine, School of Medicine, Yale University, 295 Congress Avenue, room 343, New Haven, CT, 06536-0812, USA Yuri Y. Gleba ICON Genetics AG, Biozentrum Halle, Weinbergweg 22, 06120 Halle, Germany Tasuku Honjo Faculty of Medicine, Department of Medical Chemistry, Kyoto University, Sakyo-ku, Yoshida, Kyoto 606- 8501, Japan Yoshihiro Kawaoka School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706, USA Bernard Malissen Centre d'Immunologie de Marseille-Luminy, Parc Scientifique de Luminy, Case 906, 13288 Marseille Cedex 9, France Fritz Melchers Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany Michael B. A. Oldstone Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA Rino Rappuoli Novartis Vaccines, Via Fiorentina 1, Siena, 53100, Italy Peter K. Vogt Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, BCC-239, La Jolla, CA 92037, USA Honorary Editor: Hilary Koprowski Biotechnology Foundation, Inc. 119 Sibley Avenue 19003 Ardmore, PA USA For further volumes: http://www.springer.com/series/82 Ralf Bartenschlager Editor Hepatitis C Virus: From Molecular Virology to Antiviral Therapy Responsible Series Editor: Peter Vogt 1 3 Editor Prof. Dr. Ralf Bartenschlager Department for Infectious Diseases Molecular Virology University of Heidelberg Heidelberg Germany ISSN 0070-217X ISBN 978-3-642-27339-1 ISBN 978-3-642-27340-7 (eBook) DOI 10.1007/978-3-642-27340-7 Springer Heidelberg New York Dordrecht London Library of Congress Control Number: 2013932128 © Springer-Verlag Berlin Heidelberg 2013 This work is subject to copyright. 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Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Preface Hepatitis C has long been regarded as the ‘silent epidemic’. Although there is some truth in this statement that reflects the mostly asymptomatic course of infec- tion and the low perception of the disease in the general public, the situation has changed profoundly in the last couple of years. On one hand this is due to the increasing awareness of chronic hepatitis C, especially as improved therapy options become available and are announced in press releases; on the other hand enormous progress has been made in our understanding of the molecular and cel- lular biology of the hepatitis C virus (HCV), which starts to put HCV into the position of a role model for many other, especially plus-strand RNA viruses. In these respects, the history of hepatitis C is a success story, which started in 1989 with the first molecular clone of the HCV genome and culminated in the approval of the first in class selective antiviral therapy in 2011, which increased cure rates substantially; and this is not the end of the story as further improved antiviral therapeutics will become available soon, most likely curing the majority of HCV- infected individuals. Advances in HCV-specific therapy are tightly linked to progress made in basic research that lead to the establishment of robust and easy to handle cell culture systems and unravelled the basic principles of the HCV replication cycle. Given this tremendous advancement, the time was ripe to put together a book dealing with the multiple aspects of the viral replication cycle, the interaction of HCV with the host cell, the viral countermeasures to overcome innate and adaptive immune responses, the development of antiviral therapies and their implementa- tion into daily clinical practice. Moreover, the recent identification of HCV-related genomes in dogs and horses raises speculations on the possible origin of HCV and its penetration into the human population. To cover these different aspects, I had the privilege to gather a group of dis- tinguished colleagues and leaders in the HCV field, who inspite of their busy schedule accepted the invitation to contribute book chapters. In this way it became possible to generate a comprehensive and very timely overview of the multiple facets of HCV and hepatitis C. Clearly, the focus of this book is on the molecular and cellular principles underlying the viral replication cycle. Nevertheless, the book would have been incomplete without proper description of the cell biol- ogy of virus–host interaction, which includes immune responses as well as v vi Preface HCV-associated pathogenesis. Finally, most of these discoveries were inevitably linked to the development of cell culture and animal models that also provided essential tools for drug discovery. I want to thank all the authors for their excellent contributions, their tremen- dous efforts, and great support. In addition, I want to thank the members in my laboratory, who provided valuable help in reading and editing individual chapters. Without this support, the book would not have become reality. On a final note, I very much hope that the reader will find this book a valuable source of informa- tion about HCV and enjoys reading the chapters as much as I did. Ralf Bartenschlager Contents The Origin of Hepatitis C Virus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Peter Simmonds Cell Culture Systems for Hepatitis C Virus ......................... 17 Eike Steinmann and Thomas Pietschmann Animal Models for Hepatitis C ................................... 49 Eva Billerbeck, Ype de Jong, Marcus Dorner, Cynthia de la Fuente and Alexander Ploss Hepatitis C Virus Entry ......................................... 87 Mirjam B. Zeisel, Daniel J. Felmlee and Thomas F. Baumert Hepatitis C Virus Proteins: From Structure to Function .............. 113 Darius Moradpour and François Penin Hepatitis C Virus RNA Translation ................................ 143 Michael Niepmann Hepatitis C Virus RNA Replication ................................ 167 Volker Lohmann Virion Assembly and Release ..................................... 199 Brett D. Lindenbach Innate Immune Responses to Hepatitis C Virus ..................... 219 John W. Schoggins and Charles M. Rice Adaptive Immune Responses in Hepatitis C Virus Infection ........... 243 Christoph Neumann-Haefelin and Robert Thimme vii viii Contents Liver Injury and Disease Pathogenesis in Chronic Hepatitis C ......... 263 Daisuke Yamane, David R. McGivern, Takahiro Masaki and Stanley M. Lemon Hepatitis C Virus-Specific Directly Acting Antiviral Drugs ............ 289 Leen Delang, Johan Neyts, Inge Vliegen, Sergio Abrignani, Petra Neddermann and Raffaele De Francesco Treatment of Chronic Hepatitis C: Current and Future ............... 321 Jean-Michel Pawlotsky Index ......................................................... 343 The Origin of Hepatitis C Virus Peter Simmonds Abstract The origin of hepatitis C virus (HCV) can be conceptualised at several levels. Firstly, origins might refer to its dramatic spread throughout the Western world and developing countries throughout the twentieth century. As a blood- borne virus, this epidemic was fuelled by new parenteral transmission routes associated with medical treatments, immunisation, blood transfusion and more recently injecting drug use. At another level, however, origins might refer to the immediate sources of HCV associated with its pandemic spread, now identified as areas in Central and West sub-Saharan Africa and South and South East Asia where genetically diverse variants of HCV appear to have circulated for hun- dreds of years. Going back a final step to the actual source of HCV infection in these endemic areas, non-human primates have been long suspected as harbour- ing viruses related to HCV with potential cross-species transmission of variants corresponding to the 7 main genotypes into humans. Although there is tempting analogy between this and the clearly zoonotic origin of HIV-1 from chimpanzees in Central Africa, no published evidence to date has been obtained for infection of HCV-like viruses in either apes or Old World monkey species. Indeed, a radical re- think of both the host range and host-specificity of hepaciviruses is now required following the very recent findings of a non-primate hepacivirus (NPHV) in horses Contents 1 HCV Genetic Diversity and Genotype Classification .......................................................... 2 2 The Recent Spread of HCV ................................................................................................. 5 3 Endemic Circulation of HCV .............................................................................................. 6 4 Origins of Human Infections and HCV Homologues in Other Mammals ............................................................................................................... 8 5 Concluding Thoughts ........................................................................................................... 11 References .................................................................................................................................. 12 P. Simmonds (*) Infection and Immunity Division, Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh EH25 9RG, UK e-mail: [email protected] R. Bartenschlager (ed.), Hepatitis C Virus: From Molecular Virology 1 to Antiviral Therapy, Current Topics in Microbiology and Immunology 369, DOI: 10.1007/978-3-642-27340-7_1, © Springer-Verlag Berlin Heidelberg 2013 2 P. Simmonds and potentially in dogs. Further research on a much wider range of mammals is needed to better understand the true genetic diversity of HCV-like viruses and their host ranges in the search for the ultimate origin of HCV in humans. This review is written at a highly significant time in evolutionary studies of HCV and its origins. The discovery of closely related viruses to human HCV in horses and possibly dogs termed non-primate hepacivirus (NPHV) (Burbelo et al. 2012; Kapoor et al. 2011) throws an entirely new light on the species dis- tribution of hepaciviruses and their host range. Despite the significance of these very recent discoveries, however, in many ways it is a particularly difficult time to write a review of HCV origins and evolutionary history. Frequent infection of horses worldwide with a virus reasonably similar to HCV breaks a key assump- tion of much previous research that the closest relative of HCV would be found in non-human primates. In its place we now have total uncertainty; domestic horses seem an incongruous host species and the suspicion must be that hepaciviruses are much more widely distributed in other mammals. At present, however, we simply do not know what these are. More importantly, we do not know whether viruses more similar to human HCV than NPHV exist and what species these may infect. Discovering a zoonotic source for the epidemic of HCV infection that has swept through the human population in the last century would be a truly important step in our understanding of host relationships, adaptation and pathogenicity. This review of HCV origins therefore concentrates initially on the better character- ised recent epidemic transmission of HCV in the twentieth century and the existence of suspected source areas for infection in sub-Saharan Africa and South-East Area. Some aspects of the much less well understood history of HCV before this recent spread will be speculatively discussed, as will the existence of HCV-like viruses in non-human species. Inevitably any comments made about the latter will, through fur- ther research, be revealed as either hopelessly cautious or naively overstated in a very short space of time, errors for which I apologise in advance. However, the nfi dings cannot be simply omitted from a review with this title and I hope that they spur a greater interest in the wider group of hepaciviruses and whether the attributes of HCV that make it such an important human pathogen (persistence and hepatotropism) are shared with other members of the genus. 1 HCV Genetic Diversity and Genotype Classification HCV is classified as the type member of the genus Hepacivirus within the virus family Flaviviridae (Fig. 1) (Bukh 1995; Simmonds et al. 1993, 2005). Although variants of HCV show substantial genetic diversity from each other, the 7 cur- rently classified genotypes are all classified as one species under current ICTV rules notwithstanding their considerably antigenic variability and geographical differences in distribution (Simmonds et al. 2011). Until recently, the only other virus classified as a hepacivirus was GBV-B, a virus recovered from a laboratory