Chapter Abstracts of Cytomegaloviruses (Volume I)

Publisher: Caister Academic Press
Editor: Matthias J. Reddehase Institute for Virology, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany
(with the assistance of Niels A.W. Lemmermann)
Publication date: April 2013
Full details of this book: Cytomegaloviruses (Two Volume Box Set)
Chapter Abstracts: Volume I     Volume II

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Preface From Protozoan to Proteomics
Matthias J. Reddehase
No abstract is available for the Preface

Chapter I.1 Comparative Genomics of Primate Cytomegaloviruses
Andrew J. Davison, Mary Holton, Aidan Dolan, Derrick J. Dargan, Derek Gatherer and Gary S. Hayward
The subfamily Betaherpesvirinae contains four genera and three species not yet assigned to genera. CMVs belong to this subfamily, and are usually reckoned to consist of primate viruses (such as HCMV) in the genus Cytomegalovirus, rodent viruses (such as MCMV) in the genus Muromegalovirus, and two of the unassigned viruses (GPCMV and tupaiid herpesvirus 1). In this chapter, we focus primarily on members of the genus Cytomegalovirus, which infect apes (including humans) and Old and New World monkeys. The genomes of nine of these viruses, representing six species, have been sequenced fully. They are distinguished by being among the largest and most complex in the family Herpesviridae, by exhibiting an extraordinary degree of interspecies and interstrain variation, and by all having suffered functional losses via mutation. These characteristics continue to contribute to the fascination and challenge of CMV genomics.

Chapter I.2 Molecular Evolution of Murine Cytomegalovirus Genomes
Alec J. Redwood, Geoffrey R. Shellam and Lee M. Smith
Cytomegaloviruses have co-evolved with their hosts since the mammalian radiation. The MCMV genome appears to be highly conserved and unlike the HCMV genome contains no large-scale deletions and rearrangements following serial in vitro passage. The genome of MCMV is both highly conserved and highly variable. The central regions of the genome, containing the betaherpesvirus and herpesvirus conserved genes, are highly conserved. However, significant variation occurs in species-specific genes at genomic termini, where the known and putative immune evasion genes reside. Variation in the MCMV genome consists of presence/absence polymorphisms in individual genes, grouping of genes into specific genotypes and random nucleotide diversity across the genome. However, much of the genotypic variation is under strong purifying selection indicating that these genotypes are fixed and conserved at the population level. The individual genotypes are either known to, or are likely to, target variant host gene products. Consequently, replication of MCMV is likely to be viral strain dependent and reflect the particular repertoire of genes encoded by the infecting strain. A total of 22 MCMV genes are genotypic, indicating considerable potential for variation in the MCMV population. This variation likely reflects genetic heterogeneity in the target population and suggests exquisite adaptation of the virus to its host.

Chapter I.3 Manipulating CMV Genomes by BAC Mutagenesis: Strategies and Applications
Zsolt Ruzsics, Eva M. Borst, Jens B. Bosse, Wolfram Brune and Martin Messerle
Cloning of a CMV genome as a BAC was reported for the first time more than a decade ago, and since then this approach has virtually opened the avenue for unrestricted mutagenesis of CMVs. This chapter gives an overview of recent developments in BAC-based mutagenesis techniques and their application to specific questions of CMV biology. One focus is on mutagenesis of essential CMV genes and the design of complementation strategies, as well as on conditional CMVs that allow the analysis of this class of viral genes in vitro and in vivo.

Chapter I.4 Human Cytomegalovirus Metabolomics
Joshua D. Rabinowitz and Thomas Shenk
Metabolic changes at the whole organism and cellular levels have been described for many diseases, and the alterations often underlie disease progression. Known metabolites can be quantified by using liquid chromatography to fractionate a complex mixture of compounds with analysis of the output by mass spectrometry. This approach has been applied to quantify steady state levels of metabolites as well as to monitor the flux of isotopically labeled metabolites through pathways in human cytomegalovirus-infected fibroblasts. Cytomegalovirus hijacks cellular metabolism, markedly inducing flux through much of central carbon metabolism, including glycolysis, nucleotide metabolism, the tricarboxylic acid cycle and the fatty acid metabolic enzyme acetyl-CoA carboxylase. This chapter details the metabolic changes that accompany infection, discusses the current understanding of mechanisms underlying the changes, and considers the physiological roles of the changes in human cytomegalovirus replication and spread.

Chapter I.5 Cytomegalovirus-encoded miRNAs
Meaghan H. Hancock, Igor Landais, Lauren M. Hook, Finn Grey, Rebecca Tirabassi and Jay A. Nelson
MicroRNAs (miRNAs) represent an important class of small regulatory RNAs regulate cellular processes including development and malignancies. Since the discovery that viruses encode miRNAs over 240 viral miRNAs have been identified primarily in the herpesvirus family. The cytomegalovirus (CMV) family encodes multiple miRNAs encoded throughout the viral genome. Recent work has shown that the CMV miRNAs regulate expression of both viral and cellular genes including the CMV immediate early gene 1 (IE1) and cellular genes involved in immune recognition and cell cycle regulation. In this chapter we will review our current knowledge of the targets and function of CMV encoded miRNAs.

Chapter I.6 Cytomegalovirus Proteomics
Patrizia Caposio, Daniel N. Streblow and Jay A. Nelson
Proteomics is the large-scale study of proteins, particularly their structure and interaction. In this chapter we will discuss the results obtained using a proteomic approach to analyse what is secreted from cytomegalovirus infected cells: the composition of the viral and subviral particles as well as the cellular factors that are involved in the viral pathogenesis. In the previous edition we described the viral and cellular proteins that compose the infectious HCMV virion, the entry competent, non-replicating viral particles such as Dense Bodies (DBs) and Non-Infectious Enveloped Particles (NIEPs). Using a gel-free 2-D capillary liquid chromatography (LC)-MS/MS and a Fourier transform ion cyclotron resonance (FTICR) mass spectrometry we were able to identify the relative abundance of viral and cellular proteins in purified HCMV particles. The first part of this chapter will be an up-date of the literature that has been published in these last few years on the structure and composition of the viral particles. The second part of the chapter will be dedicated to the analysis of the cellular factors secreted from infected cells that act in a paracrine fashion to enhance wound healing (WH) and angiogenesis (AG) associated with the development of long term diseases like atherosclerosis, transplant vascular sclerosis (TVS), chronic allograft rejection (CR) and glioblastoma.

Chapter I.7 A Systems Pathway View of Cytomegalovirus Infection
Peter Ghazal, Alexander Mazein, Steven Watterson, Ana Angulo and Kai A. Kropp
This chapter discusses the use of systems biology towards understanding the combinatorially complex set of molecular interactions that underpin the infection process by CMV. A hallmark of systems biology is the elucidation of pathways rather than single gene or protein activities. This generally involves the use of bioinformatics and computational modelling to analyse unbiased high throughput data such as those derived from whole genome sequencing, genome-wide transcriptomics, proteomics and metabolomics. The emerging studies in the area of CMV systems biology have to date underscored the requirement for host-dependencies on transcription factor networks, cell signalling, metabolism and cellular trafficking. Here we consider at the systems pathway level the importance of host-dependency and host-protection pathways in regulating the CMV transcription-replication cycle.

Chapter I.8 Virus Entry and Activation of Innate Defense
Adam L. Feire and Teresa Compton
All viruses must deliver their genomes to host cells to initiate infection. The cell plasma membrane serves as an initial barrier that must be crossed if an infection is going to take place. This chapter will summarize what is known about the entry pathway of human cytomegalovirus (HCMV) with certain parallels and commonalities noted between HCMV and other betaherpesviruses. The roles of HCMV envelope glycoproteins in mediating critical virus entry events such as attachment and fusion as well as the current knowledge of the identification of cellular receptors that serve as entry mediators will also be described. This chapter will also discuss the entry-associated innate antiviral response and the emerging role of signaling pathways in the early events in infection. Lastly, we will examine how virus entry and innate antiviral response may be coordinated.

Chapter I.9 Pre-immediate Early Tegument Protein Functions
Robert F. Kalejta
As virions disassemble during viral entry, they must expertly navigate and manage the complex and unwelcoming environments they encounter in order to successfully infect host cells. Herpesviruses incorporate proteins into their virions in a layer between the capsid and envelope termed the tegument to assist in this hostile takeover. When delivered to infected cells subsequent to membrane fusion, tegument proteins begin to facilitate viral infection after entry but before immediate early (IE) gene expression (referred to as the pre-IE stage of infection). Tegument-delivered proteins mediate capsid migration through the cytoplasm to nuclear pore complexes and the transmission of the genome into the nucleus. Furthermore, they modulate viral transcription, and help infected cells avoid all three classes of immune function (intrinsic, innate and adaptive). While they are most often studied during lytic infections, a new appreciation for the role that the proper regulation of tegument-delivered protein function may play during viral latency is emerging. Here the pre-IE functions of tegument proteins during both lytic and latent infections are reviewed and analyzed.

Chapter I.10 Major Immediate-Early Enhancer and Its Gene Products
Jeffery L. Meier and Mark F. Stinski
CMV major immediate-early (MIE) gene expression activates the viral replicative cycle in both acute and reactivation infections and is greatly restricted in latent infection. Specific signaling cascades, transcriptional regulatory hierarchies, and cis-regulatory codes govern the initiation efficacy, magnitude, and sustainability of MIE gene transcription. The MIE enhancer/promoter, a major determinant in viral fitness, is at the heart of this control. It is equipped with complex regulatory circuitry that integrates diverse viral, cellular, and environmental cues. The MIE genes via differential RNA splicing produce a set of multifunctional proteins that function directly in advancing the viral life cycle. CMV-induced disease genesis is driven by the regulatory mechanisms underlying both the expression of the MIE genes and the actions of the MIE gene products. A better understanding of the MIE enhancer and its gene products could potentially spawn novel strategies for preventing CMV-related disease.

Chapter I.11 Multifaceted Regulation of Human Cytomegalovirus Gene Expression
Marco Thomas, Nina Reuter and Thomas Stamminger
Research of the last two decades revealed that human cytomegalovirus (HCMV) developed a multitude of sophisticated mechanisms to usurp and manipulate the cellular gene expression machinery in order to achieve efficient viral protein synthesis. Furthermore, there is increasing evidence that the virus has to antagonize cellular restriction factors in order to avoid a silencing of viral transcription. This chapter summarizes our present knowledge on how viral regulatory proteins modulate chromatin structure, promoter activities, transcriptional elongation, RNA processing and mRNA export. Interestingly, as exemplified by the pleiotropic effector pUL69 of HCMV, specific viral regulatory proteins appear to be able to affect different cellular machineries, thus providing evidence for an extensive interconnection between transcriptional and post-transcriptional regulatory processes.

Chapter I.12 Intracellular Sorting and Trafficking of Cytomegalovirus Proteins during Permissive Infection
Anamaris M. Colberg-Poley and Chad D. Williamson
As with most DNA viruses, which require nuclear and cytoplasmic phases of virion maturation, proper and coordinated trafficking of viral proteins is crucial for the CMV lifecycle. Trafficking of CMV proteins enables jumpstarting its infection, partly determines whether lytic or latent infection is established, promotes nuclear and cytoplasmic assembly of virions, and enhances their stability and egress. To allow complex processes including viral DNA replication, packaging, nuclear and cytoplasmic egress, trafficking of CMV proteins is temporally and spatially regulated by modifications, particularly phosphorylation, and by interactions between viral or cellular proteins. Thus, orchestrated recruitment and colocalization of necessary components to enable functions are assured. In addition to conventional nuclear and cytoplasmic trafficking of viral proteins, HCMV encodes an antiapoptotic UL37 exon 1 protein or viral mitochondria-localized inhibitor of apoptosis, which circuitously traffics from the ER to mitochondria and through ER subdomains known as mitochondria-associated membranes. By this unconventional trafficking, HCMV is able to commandeer ER-mitochondrial cross-talk as well as mitochondrial functions, metabolism, antiviral responses, and apoptosis. The importance of proper intracellular trafficking of some key HCMV proteins such as those required for its DNA replication and assembly is supported by the deleterious effects of their inhibition on HCMV permissive growth.

Chapter I.13 Morphogenesis of the Cytomegalovirus Virion and Subviral Particles
Wade Gibson and Elke Bogner
Formation and maturation of the cytomegalovirus capsid is reviewed. Recent information about protein-protein interactions involved in capsid assembly, molecular interactions relating to the mechanism of DNA packaging, and the sequence of events in primary envelopment is considered as it establishes similarities and reveals differences between CMV and other herpesviruses.

Chapter I.14 Exploitation of Host Cell Cycle Regulatory Pathways by HCMV
Deborah H. Spector
Successful replication of HCMV requires the deployment of multiple approaches to commandeer the host cell machinery and create a cellular milieu that is optimal for viral gene expression, DNA replication, and formation of infectious progeny. The complex regulatory network that drives cell cycle progression provides a rich source of factors that can be co-opted and combined in different ways to tailor the host cell's environment to meet the needs of the virus for productive infection. To this end, HCMV dramatically alters cell cycle regulatory pathways, leading to cell cycle arrest. These alterations begin as soon as the viral particle enters the cell and continue throughout the entire replicative cycle. The molecular mechanisms underlying the viral-mediated effects operate at multiple levels, including altered RNA transcription, inhibition of cell DNA synthesis, changes in the levels and activity of cyclin dependent kinases as well as other cellular kinases involved in cell cycle control, modulation of protein stability through targeted effects on the ubiquitin-proteasome degradation pathway, and movement of proteins to different cellular locations. This chapter will focus on the interplay between the viral and cellular factors and the mechanisms utilized to effect these changes as they relate to the cell cycle.

Chapter I.15 Cell Death Pathways Controlled by Cytomegaloviruses
A. Louise McCormick and Edward S. Mocarski
Cytomegalovirus (CMV) deploys multiple strategies to overcome host intrinsic, innate, and adaptive responses that limit infection by triggering cell death. Multiple cell death suppressors are encoded by cytomegaloviruses infecting humans, monkeys and rodents. The viral inhibitor of caspase activation (vICA) and even the viral mitochondrial-localized inhibitor of apoptosis (vMIA) represent evolutionarily conserved strategies, whereas viral inhibitor of receptor-interacting protein kinase (RIP) activation (vIRA), the mitochondrial complex I-associated b2.7 RNA and other viral gene products whose mechanisms are not fully understood, appear to have evolved independently in primate and rodent CMVs. Initiators, effectors and interactions between CMV-induced cell death pathways have begun to emerge, through studies in cell culture and intact animals. It has become very clear that many cell death pathways are targeted by CMV-encoded cell death suppressors. Indeed, this subfamily of viruses has provided fundamental insights into pathogen-triggered regulated cell death pathways in mammals. Whereas both intrinsic and extrinsic caspase-dependent apoptosis was well-established, studies in CMV brought serine protease-dependent programmed cell death and RIP3 programmed necrotic death pathways to the fore. Virus-encoded cell death suppressors contribute resistance to cell stress as well as resistance to disruption of critical metabolic and respiratory activities. Challenges for investigators interested in this area continue to be integration of findings using diverse viral strains that impact metabolic and stress pathways with seemingly subtle differences.

Chapter I.16 Cytomegaloviruses and Interferons
Mirko Trilling and Hartmut Hengel
Interferons (IFNs) comprise a family of three different subtypes (I, II and III) of related cytokines which share their potent immuno-stimulatory and antiviral function. IFN secretion is initiated by synchronous activation of distinct classes of transcription factors (ATF/cJun, IRFs, NF-κB) upon recognition of conserved pathogen-associated molecular patterns (PAMPs) by germ-line-encoded pathogen recognition receptors (PRRs). Binding of the transcription factors to the ifn-b promoter/enhancer assembles the IFN enhanceosome, leading to IFN transcription. Secreted IFNs signal in an autocrine and paracrine manner via Jak-STAT signal transduction pathways stimulating a far-reaching transcriptional program of >300 differentially expressed genes to orchestrate intrinsic, innate and adaptive immunity. The intimate co-adaptation of cytomegaloviruses with their respective host species led to the evolution of multiple viral countermeasures which mitigate the antiviral effect of IFNs. The number of identified HCMV- and MCMV-encoded gene products interfering with IFN induction, IFN receptor signalling or IFN effector functions, is steadily growing. This review aims to provide a snapshot of our current understanding of the balance of power between pro- and antiviral measures positioned between CMV and the host IFN system. Given the immense selective pressure elicited by IFNs, it is tempting to speculate that IFNs have driven CMV to evolve a high number of antagonistic genes ensuring the complex counterbalance with IFNs and promoting CMV replication in an IFN containing environment. Counterintuitively, CMV appears also to exploit IFN induced transcription to enhance its gene expression under appropriate conditions.

Chapter I.17 Cytomegalovirus Inter-Strain Variance in Cell-Type Tropism
Barbara Adler and Christian Sinzger
Cytomegaloviruses (CMVs) are host species-specific pathogens that cause life-long persistent infections. Under conditions of reduced immune responses CMVs can cause acute systemic infections with replication in virtually any organ. The broad organ tropism is based on an equally broad range of target cell types. Epithelial cells, fibroblasts, endothelial cells and smooth muscle cells are the major target cells that support highly productive HCMV infection. Hepatocytes, trophoblasts, neurons, macrophages and dendritic cells are also susceptible to the full replication cycle of HCMV but are apparently less productive. Granulocytes and monocytes are non-productively infected by HCMV but are assumed to contribute to hematogenous dissemination as passive vehicles. Glycoprotein complexes containing gH-gL were identified as major determinants of the cell tropism of HCMV. They are assumed to recognize entry receptors and to trigger fusion of viral and cellular membranes during entry either directly at the plasma membrane or within endosomes. Virus strains that only incorporate gH-gL-gO in their envelope have a restricted target cell range excluding endothelial cells, epithelial cells and leukocytes whereas strains that also incorporate gH-gL-pUL128-pUL130-pUL131A have an extended target cell range including these cell types. HCMV progeny of the latter strains consists of distinct populations containing either high levels or low levels of the gH-gL-pUL128-pUL130-pUL131A complex thus allowing cells to navigate virus progeny by selectively releasing or retaining virion populations that differ in their tropism.

Chapter I.18 Molecular Basis of Cytomegalovirus Host Species Specificity
Wolfram Brune
Cytomegaloviruses (CMVs) are highly species-specific as they replicate almost exclusively in cells of their natural host species. However, the molecular basis of species specificity remains poorly understood. In cells of a foreign host a post-penetration block to viral gene expression and genome replication appears to restrict viral replication and spread. In some cases, infected cells of a foreign host undergo programmed cell death, indicating that apoptosis acts as a cellular antiviral defense mechanism to prevent viral replication. A few recent studies suggested that mediator and effector molecules of the interferon system and antiviral defenses operating at PML nuclear bodies (PML-NBs) might also be involved in restricting the host range of CMVs. Moreover, a recently isolated spontaneous mutant of murine CMV, which is capable of replicating to high titers in human cells, provided a new opportunity to study the mechanisms of CMV host species specificity. In this spontaneously adapted virus, mutations in the region encoding the viral Early1 (E1) proteins were found to be responsible for the extended host range phenotype. Further investigations of the CMV host species specificity should lead to a better understanding of the viral replication machinery, interfering host cell factors, and viral countermeasures.

Chapter I.19 Epigenetic Regulation of Human Cytomegalovirus Gene Expression: Impact on Latency and Reactivation
Matthew Reeves and John Sinclair
The myeloid lineage is now accepted to be an important site in vivo for the carriage of latent HCMV genomes, but the mechanisms underlying how the latent state is maintained and how latent virus reactivates are still far from clear. In this review, we discuss how analyses of promoter binding proteins and post-translational modifications of histones on viral promoters during virus infection have led to an understanding that the higher-order chromatin structure around the viral major immediate-early promoter region has profound effects on the control of viral latency and reactivation. We further discuss the role of chromatin during lytic infection and how this may also give insights into the cellular mechanisms important for the establishment and control of latent infection.

Chapter I.20 Transcription Associated with Human Cytomegalovirus Latency
Barry Slobedman, Selmir Avdic and Allison Abendroth
Following primary infection, and despite the induction of a massive and sustained anti-viral immune response, human cytomegalovirus (HCMV) is never completely cleared from the human host, but rather establishes a life-long latent infection, during which time infectious virus becomes undetectable. Reactivation from latency results in re-initiation of productive virus replication, a process which often results in life-threatening disease in immunosuppressed individuals. The capacity of HCMV to establish, maintain and reactivate from a latent state contributes significantly to the success of this virus as a human pathogen, yet the molecular basis for latency remains relatively poorly understood. A major component of understanding how HCMV functions during latency has been identification and characterization of viral genes which are expressed during this phase of infection, with the underlying hypothesis being that viral genes expressed during latency are likely to play fundamental roles that enable HCMV to persist in a latent state in the healthy human host. Here we will focus on HCMV gene expression during latency, highlighting our current understanding of this challenging field, and as well as areas which will require further focus. It is hoped that a better understanding of viral determinants of latency will provide a rational basis for the development of novel therapies to target HCMV during the latent phase, and so limit or prevent the devastating disease that often arises following reactivation from latency.

Chapter I.21 Myeloid Cell Recruitment and Function in Cytomegalovirus Dissemination and Immunity
Lisa P. Daley-Bauer and Edward S. Mocarski
Cytomegalovirus pathogenesis, dissemination and immunity are tied to the behaviour of myelomonocytic cells. Investigations of the roles of monocyte subsets in the dissemination of cytomegalovirus revealed that the MCMV-encoded chemokine, MCK2, controls recruitment patterns of the two major monocyte subsets (inflammatory and patrolling) to sites of infection. Monocytes give rise to both macrophages and dendritic cells that populate tissues. Mice deficient in the chemokine axis (CCR2 and CCL2 /MCP-1) do not support inflammatory monocyte emigration from bone marrow. Inflammatory monocyte-derived lineages, which are nonpermissive for MCMV, are dispensable for pathogenesis and dissemination as well as for the establishment of latency set-points. Nevertheless, recruitment of inflammatory monocytes is enhanced by elaboration of MCK2 and impairs the CTL response to delay viral clearance. In contrast, patrolling monocytes support MCMV replication and contribute to dissemination patterns in the host. Studies in CX₃CR1-deficient infected mice show reduced viral dissemination to salivary glands, consistent with the reduced survival of patrolling monocytes in these animals. HCMV studies suggest myelomonocytic progenitor cells, including inflammatory and patrolling monocyte subsets, are associated with acute as well as latent infections. MCMV latency in mice occurs in myeloid as well as epithelial and endothelial cell lineages. In this chapter, we review the current understanding of myelomonocytic lineage cells in the establishment of cytomegalovirus infections based on human and murine studies.

Chapter I.22 Immune Surveillance of Cytomegalovirus Latency and Reactivation in Murine Models: Link to 'Memory Inflation'
Christof K. Seckert, Marion Grieβl, Julia K. Büttner, Kirsten Freitag and Niels A.W. Lemmermann and Mary A. Hummel, Xue-Feng Liu and Michael I. Abecassis and Ana Angulo and Martin Messerle and Charles H. Cook and Matthias J. Reddehase
Cytomegalovirus (CMV) disease with cytopathogenic viral replication and multiple organ involvement is typically confined to the immunocompromised or immunologically immature host. In the immunocompetent host, productive primary CMV infection is efficiently controlled, and is eventually resolved at all tissue sites, by well-orchestrated mechanisms of the innate and adaptive branches of the immune system in due time to prevent overt disease manifestations. At the earliest stages of an acute infection, NK cells rapidly followed by virus epitope-specific CD8⁺ T cells play major antiviral roles, and recent findings indicate that these two effector systems are cross-talking for keeping the virus in check despite the fact that during co-speciation with their specific host species all CMVs have evolved strategies to reduce the infected cells' susceptibility to both NK cell-mediated and CD8⁺ T cell-mediated antiviral immune functions. The outcome of this virus-host struggle for survival is a ceasefire in which the viral genome is not cleared but is maintained for the lifetime of the individual host in the presence of a fully developed, protective antiviral 'immune memory' without producing infectious viral progeny but retaining the functional capacity to complete the productive replication cycle under conditions of waning immune surveillance and transcription factor-mediated viral gene desilencing as a result of inflammatory cytokine signaling. These phenomena, known as 'latency' and 'reactivation' are biological hallmarks that CMVs share with all other members of the herpesvirus family. Notably, while immune surveillance appears to play a central role in maintaining latency, that is in preventing the virus from completing the productive replication cycle and, if it nevertheless should happen locally, preventing recurrent virus from further rounds of infection and spreading, increasing evidence suggests that the establishment of latency on the molecular level may not be immune-driven. Rather, molecular latency results from the cells' intrinsic antiviral defense by epigenetic silencing of viral gene expression associated with rapid circularization and chromatinization of incoming linear viral genomes within repressive nuclear domains. In this view, 'latency' is the default state, whereas productive infection, from the hosts' perspective, is the accident when viral genomes evade epigenetic silencing, with the chance for this being dependent on cell type, cell differentiation stage, cell cycle stage, and an overall nuclear environment that favors open chromatin structures, collectively defining what we describe as 'permissively' for productive infection. It is proposed that during latency stochastic episodes of promiscuous desilencing of single or combinatorial sets of viral genes can lead to the expression of transcripts (transcript expressed in latency, TEL), which, when translated into proteins, can result in the presentation of antigenic peptides sensed by tissue-patrolling effector-memory T cells. Importantly, promiscuous gene desilencing, unlike reactivation, does not usually initiate the productive viral replication cycle and can affect any viral gene regardless of its temporal expression in the kinetic classes immediate-early (IE), early (E) and late (L), and regardless of the function it takes during lytic infection. It is our current understanding that these limited desilencing episodes are the molecular motor that drives the CMV-typic expansion of T cells, of CD8⁺ T cells in particular, a phenomenon commonly known under the catchphrase 'memory inflation'. The 'classical era' of research in diverse murine models of CMV latency and reactivation has been reviewed by Jordan (1983) and authors of this book chapter have provided updates (Hummel and Abecassis, 2002; Reddehase et al., 2002; 2008). Here, independent research groups have joined to review their more recent results and current views on CMV latency and reactivation based on murine CMV models with focus on neonatal infection, hematopoietic (stem) cell transplantation (HCT), solid organ transplantation (SOT), and sepsis.

Chapter I.23 Humanized Mouse Models of Cytomegalovirus Pathogenesis and Latency
M. Shane Smith, Daniel N. Streblow, Patrizia Caposio, and Jay A. Nelson
The generation of mice engrafted with human hematopoietic stem cells (HSC) has allowed, for the first time, the study of human specific viruses in an in vivo setting. These humanized mouse models have been developed and improved over the past 30 years. It is now possible to achieve high levels of human cell engraftment producing human myeloid and lymphoid lineage cells. Humanized mouse models have been increasingly utilized in the study of human cytomegalovirus, a human-specific beta-herpesvirus that infects myeloprogenitor cells and establishes a life-long latency in the infected host. Upon mobilization and differentiation of infected bone marrow progenitor cells the latent virus reactivates and disseminates to other tissues. In this chapter, we review the current status of the HSC-engrafted mouse models used to study HCMV latency and reactivation. We will first highlight the role myeloid lineage cells plays in HCMV biology and then describe the types of humanized mouse models that have been used in HIV, EBV, KSHV and HCMV anti-viral therapy studies. We will then describe recent studies utilizing the latest generation of humanized mice for the study of HCMV latency and reactivation and outline the future role that these models may play in the study of human-specific viruses.

Full details of this book: Cytomegaloviruses (Two Volume Box Set)