Table Of ContentCurrent 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
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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
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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
