Latency Strategies of Herpesviruses

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2 Latency Strategies of Herpesviruses

3 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

4 Janos Minarovits Microbiological Research Group National Center for Epidemiology H-1529 Budapest Hungary Eva Gonczol Department of Virology National Center for Epidemiology H-1097 Budapest Hungary Tibor Valyi-Nagy Department of Pathology College of Medicine University of Illinois at Chicago Chicago, IL USA Library of Congress Control Number: ISBN-10: X e-isbn-10: ISBN-13: e-isbn-13: Printed on acid-free paper Springer Science+Business Media, LLC All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights springer.com

5 Preface Latency is a most remarkable property of herpesviruses that ensures the maintenance 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 transformation, tumorigenesis). In this book, we wished to review the intriguing latency strategies developed during the estimated 200-million-years-long coevolution (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 reactivation of 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 molecular 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 differentiation-dependent expression of lytic viral genes and the molecular mechanisms v

6 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 via the germline. In addition to viruses of medical interest, certain herpesviruses infecting animals are also described in this book. In Chapter 5, Julius Rajčáni 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 available data on their latency in Chapter 6. Turning to human gammaherpesviruses, Christopher M. Collins and Peter G. Medveczky focus on LANA1 (latencyassociated nuclear antigen 1), a multifunctional nuclear antigen of Kaposi s sarcoma associated herpesvirus (Chapter 7). This sequence-specific DNA binding 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 lymphocytes 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.

7 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

8 Contents Preface Acknowledgments Contributors v vii xi Chapter 1: Chapter 2: Latency Strategies of Alphaherpesviruses: Herpes Simplex Virus and Varicella-Zoster Virus Latency in Neurons Tibor Valyi-Nagy, Deepak Shukla, Herbert H. Engelhard, Jerry Kavouras, and Perry Scanlan Modulation of Apoptotic Pathways by Herpes Simplex Viruses Klára Megyeri Chapter 3: Cytomegalovirus Latency Katalin Burian and Eva Gonczol Chapter 4: Human Herpesvirus 6 and Human Herpesvirus Béla Taródi Chapter 5: Murid Herpesvirus 4 (MuHV-4): An Animal Model for Human Gammaherpesvirus Research Julius Rajčáni and Marcela Kúdelová Chapter 6: Latency Strategies of Equine Herpesviruses Laszlo Egyed Chapter 7: The Multifunctional Latency-Associated Nuclear Antigen of Kaposi s Sarcoma-Associated Herpesvirus Christopher M. Collins and Peter G. Medveczky ix

9 x Contents Chapter 8: Epstein-Barr Virus Hans Helmut Niller, Hans Wolf, and Janos Minarovits List of Abbreviations References Index

10 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, 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

11 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 Regensburg, Germany Julius Rajčáni Institute of Virology, Slovak Academy of Sciences, Dubravska 9, 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 Regensburg, Germany

12 Chapter 1 Latency Strategies of Alphaherpesviruses: Herpes Simplex Virus and Varicella-Zoster Virus Latency in Neurons TIBOR VALYI-NAGY, DEEPAK SHUKLA, HERBERT H. ENGELHARD, JERRY KAVOURAS, AND PERRY SCANLAN 1. Introduction Members of the Alphaherpesvirinae subfamily of the Herpesviridae family establish latent infections primarily in sensory neurons of the peripheral nervous system. Other general features differentiating these viruses from other herpesviruses include a relatively short reproductive cycle, rapid spread in culture, efficient destruction of infected cells, and a variable host range (reviewed in Roizman and Pellet, 2001; Whitley, 2001). In this chapter, we discuss the pathogenesis of two human alphaherpesviruses, herpes simplex virus and varicella-zoster virus, with the main objective being to review the large body of information available about the mechanisms by which these alphaherpesviruses establish latency in neurons and periodically reactivate to produce infectious virus. 2. Herpes Simplex Virus 2.1. Natural History Herpes simplex virus (HSV) belongs to the Simplexvirus genus of the Alphaherpesvirinae subfamily. It has two serotypes, herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2); both are important human pathogens. HSV-1 and HSV-2 are phylogenetically ancient viruses that have evolved together with their human host (Roizman and Pellett, 2001). Like other herpesviruses, HSV-1 and HSV-2 are well adapted to their natural host: fatal HSV infections of immunocompetent humans that do not lead to the effective transmission of the virus are relatively rare. In most cases instead, human HSV-1 and HSV-2 infections lead to a long and balanced interaction between host and virus that allows for efficient virus transmission: lifelong latent infection is established that is interrupted by episodes of viral reactivation. HSV was first isolated by Lowenstein (Lowenstein, 1919) and was classified into two serologically distinct types by Schneweiss (Schneweiss, 1962). The two serotypes can be readily distinguished genetically and biologically; however, their virion 1

13 2 T. Valyi-Nagy et al. structures are very similar to each other and by definition similar to other herpesviruses as membership in the Herpesviridae family is based on virion structure. In general, the HSV virion consists of four elements: (i) an electron-opaque core consisting of the viral double-stranded DNA genome approximately 152 kbp in size, (ii) an icosahedral proteinaceous capsid surrounding the core, (iii) an amorphous tegument surrounding the capsid, and (iv) an outer envelope exhibiting spikes on its surface (for a detailed review of HSV structure and replication, see Roizman and Knipe, 2001). The HSV genome consists of two covalently linked components: a long and a short segment. Each segment has unique sequences bracketed by inverted repeat sequences (Fig. 1.1). The HSV genome encodes at least 84 polypeptides. HSV genes are classified into at least three kinetic classes: immediate early (IE), or α; early, or β; and late, or γ (Honess and Roizman, 1974; Roizman and Knipe, 2001; Rajcani et al., 2004). HSV-1 infection of tissue culture cells is initiated by specific interactions between viral glycoproteins in the virion envelope and receptors in the cell membrane, followed by fusion of the viral envelope and cell membrane and TR L U L IR L IR S U S TR S ICP0 ICP34.5 ICP4 Primary LAT 2.0 kb LAT 1.5 kb LAT L/ST s ORFO ORFP FIGURE 1.1. Latency-associated transcripts of the herpes simplex virus genome. The location of long and short terminal and internal repeats (TR and IR), location of long and short unique (U) sequences of the genome, and the location of latency-associated transcripts relative to ICP0, ICP34.5, ICP4, and L/STs are shown.

14 Chapter 1. Latency Strategies of Alphaherpesviruses 3 translocation of the viral nucleocapsid to the cytoplasm (reviewed in Spear et al., 2000; Shukla and Sprear, 2001). Recent observations suggest that HSV may also enter cells by endocytic (Nicola et al., 2003) and phagocytosis-like (Clement et al., submitted) mechanisms. Once in the cytoplasm, the viral nucleocapsid is transported by microtubules to a nuclear membrane pore where viral genomic DNA is released into the nucleus (Sodiek et al., 1997; Ojala et al., 2000). Inside the nucleus, one of the HSV tegument proteins, VP16 (also called alpha-transinducing factor, alpha-tif and Wmw65) forms a transcriptional regulatory complex with the cellular POU (acronym for Pit-1, Oct-1, Oct-2, and Unc-86) domain transcription factor Oct-1 and the cellular cofactor host cell factor 1 (HCF-1; also known as C1, VCAF, CFF) to activate the transcription of HSV IE genes (for a recent review, see Wysocka and Herr, 2003). The transcriptional regulatory complex formed by VP16, Oct-1, and HCF binds to reiterated core enhancer TAATGARAT elements present in all IE promoters. The assembly of this complex depends on the recognition of the core enhancer (TAATGARAT) elements by Oct-1. VP16 contributes with two levels of specificity: by selective recognition of the homeodomain surface of Oct-1 and by cooperative recognition of the core enhancer element. HCF-1 in turn stabilizes the protein complex and acts as a transcriptional coactivator to mediate the activation potential of VP16 (Wysocka and Herr, 2003; Narayanan et al., 2005). VP16 contains a strong activation domain that promotes transcription through interaction with several components of the basal transcription machinery including proteins with histone acetyltransferase (HAT) activity (Utley et al., 1998; Kraus et al., 1999; Wang et al., 2000; Ikeda et al., 2002; Wysocka and Herr, 2003). The core enhancer (TAATGARAT) elements in the HSV IE promoters are flanked by binding sites for additional transcription factors including GA binding protein (GABP) and Sp1; these transcription factors can also interact with HCF-1 (Kristie and Roizman, 1984; Jones and Tjian, 1985; Triezenberg et al., 1988; Gunther et al., 2000; Vogel and Kristie, 2000). HSV encoded IE proteins include infected cell polypeptides (ICP) 0, 4, 22, 27, 47 and U s 1.5 (reviewed in Roizman and Knipe, 2001). Among these, ICP4 and ICP27 are absolutely essential for virus replication (Preston, 1979; Watson and Clements, 1980; DeLuca and Schaffer, 1985; Sachs et al., 1985; McCarthy et al., 1989). ICP4 is required for the transcription of early and late genes acting through the basal cellular transcription machinery (Coen et al., 1986). ICP27 regulates processing of viral and cellular mrna (reviewed in Phelan and Clements, 1998). ICP0, a multifunctional protein, stimulates the expression of all three classes of HSV genes and increases the probability of the virus entering lytic infection, particularly after low multiplicity of infection (MOI) (Stow and Stow, 1986; Sachs and Schaffer, 1987; Everett, 1989; Leib et al., 1989; Cai et al., 1992, 1993). The U s 1.5 transcription unit is within the coding sequence of ICP22. ICP22 is required for efficient replication of HSV in certain cultured cell types (Post and Roizman, 1981; Sears et al., 1985; Rice et al., 1995), and ICP47 interferes with antigen presentation to CD8 + lymphocytes (York et al., 1994). Thus, most IE HSV genes encode viral transcription factors, which are responsible for the

15 4 T. Valyi-Nagy et al. modification of the host cell environment for viral replication and induction of the expression of the viral early genes that in turn encode proteins important for replication of viral DNA and nucleotide metabolism. Finally, as viral DNA synthesis has been initiated, expression of the late (γ) group of viral genes is increased. These genes encode structural virion proteins. Late genes fall under two categories: early-late, or γ1 genes can be expressed without viral DNA synthesis although their expression is induced by DNA synthesis, whereas true-late, or γ 2 genes require the onset of viral DNA synthesis for their expression. Newly produced viral DNA and proteins assemble to form nucleocapsids and bud through the nuclear membrane acquiring an envelope. Productive infection of cultured cells by HSV is thought to be invariably cytolytic, and the release of newly made virions is associated with death of infected cells. It is though that both HSV toxicity and cellular responses to infection contribute to the death of the productively infected cell (Roizman and Knipe, 2001). Potential mechanisms by which HSV-1 infection leads to cellular injury involve several steps of the replication cycle including initial virion cell membrane interactions and the effects of tegument proteins and viral proteins newly expressed in the infected cells. Although HSV IE proteins are clearly cytotoxic (Johnson et al., 1992, 1994; Wu et al., 1996; Samaniego et al., 1998), some observations suggest that the effects of virion proteins in the absence of de novo viral protein synthesis are not sufficient to adversely affect cell function as UVirradiated virus and an HSV-1 mutant that does not express any of the IE proteins were reported to be nontoxic to cultured cells (Munyon et al., 1971; Samaniego et al., 1988). Mechanisms by which productive HSV-1 infection interferes with cellular metabolism include shutoff of cellular macromolecular synthesis, degradation of cellular RNA, inhibition of splicing of messenger RNA, selective degradation or stabilization of cellular proteins, and interference with the cellcycle machinery with induction of cell-cycle block in either G 1 or G 2 (reviewed in Roizman and Knipe, 2001). HSV infection leads to an upregulation of various cellular transcription factors, stress response genes, cell-cycle regulatory genes, and genes involved in apoptotic pathways (Hobbs and DeLuca, 1999; Khodarev et al., 1999; Stingley et al., 2000; Taddeo et al., 2002). HSV may induce oxidative damage to cellular lipids, proteins, and nucleic acids in infected cells (Palu et al., 1994, Valyi-Nagy et al., 2000; Milatovic et al., 2002; Valyi-Nagy and Dermody, 2005). Interaction of HSV with the cellular apoptotic machinery is complex and involves both proapoptotic and antiapoptotic viral effects (for a detailed review, see the chapter on molecular mechanisms implicated in virusinduced apoptosis by Megyeri in this volume). HSV has multiple antiapoptotic genes, and the inhibition of apoptosis is thought to be beneficial for HSV because it requires the environment of a living cell to replicate. Cellular reactions to infection that HSV needs to overcome also include silencing of viral DNA by the complex formed by CoRest/REST and histone deacetylases (HDAC) 1 and 2 and interferon (IFN) signaling. Early in infection, viral DNA and ICP0 colocalize with nuclear structures known as nuclear domain (ND) 10 (Maul et al., 1993; Maul and Everett, 1994; Everett and Maul, 1994). This colocalization appears to