Table Of ContentLatency Strategies of Herpesviruses
Latency Strategies
of Herpesviruses
Edited by
Janos Minarovits
National Center for Epidemiology
Budapest, Hungary
Eva Gonczol
National Center for Epidemiology
Budapest, Hungary
Tibor Valyi-Nagy
University of Illinois at Chicago
Chicago, Illinois, USA
Janos Minarovits Eva Gonczol
Microbiological Research Group Department of Virology
National Center for Epidemiology National Center for Epidemiology
H-1529 Budapest H-1097 Budapest
Hungary Hungary
[email protected] [email protected]
Tibor Valyi-Nagy
Department of Pathology
College of Medicine
University of Illinois at Chicago
Chicago, IL 60612-7335
USA
[email protected]
Library of Congress Control Number: 2006922572
ISBN-10: 0-387-32464-X e-ISBN-10: 0-387-34127-7
ISBN-13: 978-0387-32464-7 e-ISBN-13: 978-0387-34127-9
Printed on acid-free paper.
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Preface
Latencyis a most remarkable property of herpesviruses that ensures the mainte-
nance of their genetic information in their hosts for an extended period in the
absence of productive replication. Members of all three herpesvirus subfamilies
infecting a wide variety of target cells are able to establish latent infection, which
is associated with a restricted expression of the viral genome. Latency-associated
transcription is either confined to protein noncoding RNAs and/or protein coding
RNAs not translated in the latently infected cells or may include transcripts for
viral oncoproteins that alter host cell behavior (immortalization, malignant trans-
formation, tumorigenesis). In this book, we wished to review the intriguing
latency strategies developed during the estimated 200-million-years-long coevo-
lution (McGeoch and Davison, 1999) of Alpha-, Beta-,and Gammaherpesvirinae
and their host species. We put the main emphasis on herpesviruses infecting
humans, but we discuss relevant cases of herpesviruses infecting animals as well.
We wished to highlight immune evasion tactics used by these viruses as well as
the molecular mechanisms regulating the latent promoters of their genomes and
signals and molecular pathways resulting in reactivationof latent viral genomes.
We gave special attention to epigenetic mechanisms (DNA methylation, histone
modifications, chromatin structure) involved in cell-type-specific expression of
growth transformation–associated gammaherpesvirus genes.
The goal of this book is to bring together recent results of herpesvirus research
with special attention to latent infections. Although the chapters follow the classical
scheme with three subfamilies (Alpha-, Beta-,and Gammaherpesvirinae), we also
included special chapters dealing with important aspects of herpesvirus latency,
like the modulation of apoptotic pathways and the maintenance of latent,
episomal DNA genomes. In the first chapter, Tibor Valyi-Nagy, Deepak Shukla,
Herbert H. Engelhard, Jerry Kavouras, and Perry Scanlan describe how
alphaherpesviruses (herpes simplex virus and varicella-zoster virus) hide in
neurons, giving utmost care to the mechanisms of immune evasion and the molec-
ular biological background (including an epigenetic regulatory mechanism,
histone modification) ensuring the almost complete transcriptional silence of the
latent genomes. Next, in a special chapter, Klára Megyeri gives a detailed picture
of apoptotic pathways modulated by herpes simplex viruses. In the third chapter,
Katalin Burian and Eva Gonczol deal with the latency strategies of human
cytomegalovirus (HCMV, a betaherpesvirus) discussing the models of differen-
tiation-dependent expression of lytic viral genes and the molecular mechanisms
v
vi Preface
preventing virus production in undifferentiated cells. They give a detailed
overview of how HCMV evades innate and adaptive immune responses, too. In
Chapter 4, Béla Taródi summarizes the current knowledge on human herpesvirus
6 and 7 latency, highlighting the unique features of the latency-associated
transcripts. He pinpoints that one of these betaherpesviruses, HHV-6, can be
transmitted in infrequent cases viathe germline. In addition to viruses of med-
ical interest, certain herpesviruses infecting animals are also described in this
book. In Chapter 5, Julius Rajcˇáni and Marcela Kúdelová give a detailed
description of murid herpesvirus 4, which provides an important animal model
for human gammaherpesvirus research. Much less knowledge has accumulated
on equine alpha- and gammaherpesviruses: Laszlo Egyed compares the avail-
able data on their latency in Chapter 6. Turning to human gammaherpesviruses,
Christopher M. Collins and Peter G. Medveczky focus on LANA1 (latency-
associated nuclear antigen 1), a multifunctional nuclear antigen of Kaposi’s
sarcoma–associated herpesvirus (Chapter 7).This sequence-specific DNA bind-
ing protein plays a crucial role in the replication and maintenance of the latent,
episomal viral genomes and mediates their segregation during cell division. It is
also involved in the alteration of cellular behavior (malignant transformation).
The properties of LANA1 homologues encoded by Herpesvirus saimiri and
murine gammaherpesvirus 68 are also discussed here. In the final chapter, Hans
Helmut Niller, Hans Wolf, and Janos Minarovits review the latency strategies of
Epstein-Barr virus (EBV). EBV, a Lymphocryptovirus, hides in memory B lym-
phocytes and contributes to the development of a wide variety of neoplasms. They
describe how the expression of latent EBV genes is regulated by DNA (CpG)
methylation and how the cell-type-specific usage of latency promoters is reflected
in cell-type-specific methylation patterns of the viral genomes (epigenotypes).
They also discuss how other epigenetic mechanisms (binding of regulatory
proteins, histone modifications) leave their marks on the locus control region (LCR)
of the latent viral episome, which persists like an independent chromosomal
domain.
Janos Minarovits, M.D., D.Sc.
Eva Gonczol, M.D., D.Sc.
Tibor Valyi-Nagy, M.D., Ph.D.
Acknowledgments
This book is the result of the efforts of numerous authors, and we thank them for
their excellent contributions. We are also grateful to Judit Segesdi for her help in
arranging the figures and Dr. Hans Helmut Niller and Dr. Daniel Salamon for
proofreading the text.
Janos Minarovits, M.D., D.Sc.
Eva Gonczol, M.D., D.Sc.
Tibor Valyi-Nagy, M.D., Ph.D.
vii
Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
Chapter 1: Latency Strategies of Alphaherpesviruses:
Herpes Simplex Virus and Varicella-Zoster
Virus Latency in Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Tibor Valyi-Nagy, Deepak Shukla, Herbert H. Engelhard,
Jerry Kavouras, and Perry Scanlan
Chapter 2: Modulation of Apoptotic Pathways by Herpes
Simplex Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Klára Megyeri
Chapter 3: Cytomegalovirus Latency . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Katalin Burian and Eva Gonczol
Chapter 4: Human Herpesvirus 6 and Human Herpesvirus 7 . . . . . . . . 86
Béla Taródi
Chapter 5: Murid Herpesvirus 4 (MuHV-4): An Animal Model
for Human Gammaherpesvirus Research . . . . . . . . . . . . . . 102
Julius Rajcˇáni and Marcela Kúdelová
Chapter 6: Latency Strategies of Equine Herpesviruses . . . . . . . . . . . . 137
Laszlo Egyed
Chapter 7: The Multifunctional Latency-Associated Nuclear
Antigen of Kaposi’s Sarcoma-Associated
Herpesvirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Christopher M. Collins and Peter G. Medveczky
ix
x Contents
Chapter 8: Epstein-Barr Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
Hans Helmut Niller, Hans Wolf, and Janos Minarovits
List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
Contributors
Katalin Burian
Department of Medical Microbiology and Immunology, University of Szeged,
H-6721 Szeged, Dom ter 10, Hungary
Christopher M. Collins
Department of Microbiology and Immunology, Yerkes Regional Primate
Research Center, Emory University, Atlanta, GA 30329, USA
Laszlo Egyed
Veterinary Research Institute of the Hungarian Academy of Sciences, H-1143
Budapest, Hungaria krt 21, Hungary
Herbert H. Engelhard
Department of Pathology, College of Medicine, University of Illinois at
Chicago, 1819 West Polk Street, Room 446, Chicago, IL 60612, USA
Eva Gonczol
Department of Virology, National Center for Epidemiology, H-1097 Budapest,
Gyali út 2-6, Hungary
Jerry Kavouras
Department of Pathology, College of Medicine, University of Illinois at
Chicago, 1819 West Polk Street, Room 446, Chicago, IL 60612, USA
Marcela Kúdelová
Institute of Virology, Slovak Academy of Sciences, Dubravska 9, 84505
Bratislava, Slovak Republic
Peter G. Medveczky
Department of Medical Microbiology and Immunology and H. Lee Moffitt
Cancer Center, University of South Florida, Tampa, FL 33548, USA
Klára Megyeri
Department of Medical Microbiology and Immunology, University of Szeged,
H-6721 Szeged, Dom ter 10, Hungary
xi
xii Contributors
Janos Minarovits
Microbiological Research Group, National Center for Epidemiology, H-1529
Budapest, Pihenö u. 1, Hungary
Hans Helmut Niller
Institute for Medical Microbiology and Hygiene, Research Center, University of
Regensburg, Landshuter Str. 22, D-93047 Regensburg, Germany
Julius Rajcˇáni
Institute of Virology, Slovak Academy of Sciences, Dubravska 9, 84505
Bratislava, Slovak Republic
Perry Scanlan
Department of Pathology, College of Medicine, University of Illinois at
Chicago, 1819 West Polk Street, Room 446, Chicago, IL 60612, USA
Deepak Shukla
Department of Pathology, College of Medicine, University of Illinois at
Chicago, 1819 West Polk Street, Room 446, Chicago, IL 60612, USA
Béla Taródi
Department of Medical Microbiology and Immunology, University of Szeged,
H-6720 Szeged, Dom ter 10, Hungary
Tibor Valyi-Nagy
Department of Pathology, College of Medicine, University of Illinois at
Chicago, 1819 West Polk Street, Room 446, Chicago, IL 60612, USA
Hans Wolf
Institute for Medical Microbiology and Hygiene, Research Center, University of
Regensburg, D-93047 Regensburg, Germany
