Chapter Abstracts of Cytomegaloviruses (Volume II)

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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Chapter II.1 Synopsis of Clinical Aspects of Human Cytomegalovirus Disease
Suresh B. Boppana and William J. Britt
The spectrum of clinical disease associated with infection with human cytomegalovirus (HCMV) ranges from severe multi-organ system disease with significant morbidity and mortality to nearly an asymptomatic infection. Populations susceptible to severe HCMV infections include transplant recipients undergoing immunosuppressive therapy, individuals with untreated HIV infection, and the developing fetus. The loss of adaptive immunity in transplant recipients and HIV infected hosts represents a major risk factor for disseminated HCMV infection whereas the developmentally immaturity of immune system of the fetus has been proposed to predispose infants infected in-utero to severe infection and disease. Specific immunological determinants that predispose infection and disease remain incompletely characterized but both CD8⁺ and CD4⁺ T lymphocyte responses, antiviral antibodies, and natural cytotoxicity (natural killer cells, γδ T cells) all have been shown to have a potential role in controlling HCMV replication. The clinical expression of HCMV infection appears directly related to the immune response of the host such that immunocompromised individuals are at risk for uncontrolled virus replication and dissemination. Paradoxically, under conditions in which the adaptive immune system is severely impaired and virus replication continues unabated, a combination of viral cytopathology and host immunopathological responses arising from residual immunity appear to contribute to disease. Under specific circumstances such as in solid organ allograft recipients, immunopathological responses appear to be a major determinant in the long term outcome of allograft recipients. The mechanism(s) of disease in the HCMV infected fetus remains poorly understood perhaps because of a lack of well defined models of this infection and the hurdles inherent in the study of subclinical infections in pregnant women and silent transmission to the developing fetus. However, as in the immuocompromised host, maternal immunity and presumably, passively acquired immunity in the fetus, modify the infection and have prompted interests in developing prophylactic vaccines. However, recent studies have demonstrated that preexisting maternal immunity is incomplete in the prevention of infection and disease suggesting that approaches that induce levels of immunity that are present in naturally immune individuals may be insufficient to prevent congenital HCMV infection and disease. Selective use of currently available antiviral therapies has provided a significant improvement in outcome of HCMV infections in immunocompromised hosts.

Chapter II.2 The Epidemiology and Public Health Impact of Congenital Cytomegalovirus Infection
Michael J. Cannon, Scott D. Grosse and Karen B. Fowler
Congenital cytomegalovirus (CMV) is one of the most important causes of childhood disability in many countries. The dynamics of congenital CMV are driven by a complex interplay between factors that include the prevalence of CMV infection in the population, the frequency of viral shedding in bodily fluids, the relative importance of different transmission routes, and the incidence of CMV infection among women of reproductive age. Among children infected congenitally, many experience no disease sequelae, while others experience one or more disabilities which can vary in severity and which may be present at birth or may have a delayed onset. From a public health perspective, avenues for addressing congenital CMV include raising awareness, promoting primary prevention through behavioral change, and assessing the utility of prenatal and newborn screening.

Chapter II.2- Addendum The Economic Impact of Congenital CMV Infection: Methods and Estimates
Scott D. Grosse, Ismael R. Ortega-Sanchez, Stephanie R. Bialek and Sheila C. Dollard
Calculation of the economic burden of congenital cytomegalovirus (CMV) is needed to quantify the potential economic impact of preventive interventions. Although no preventive interventions are currently available other than hygiene education and avoidance of exposures by pregnant women, economic assessment may be needed in coming years for a CMV vaccine, prenatal screening followed by pharmacologic treatment, or newborn screening and early intervention for hearing loss and other disabilities. Economic estimates of the costs associated with the long-term consequences of congenital CMV infections are important both to demonstrate the potential benefit from the development of preventive interventions and also to assess their expected cost-effectiveness or cost-benefit once they are ready to be implemented.

Chapter II.3 Clinical Cytomegalovirus Research: Congenital Infection
Stuart P. Adler and Giovanni Nigro
The epidemiology and pathogenesis of CMV infections among pregnant women have been intensely studied over the last three decades. This chapter focuses on recent research developments related to CMV infections during pregnancy. The developments include an understanding of the pathogenesis of CMV infections, knowledge of high risk women, and potentially effective interventions to prevent maternal infections during pregnancy.

Chapter II.4 Cytomegalovirus Replication in the Developing Human Placenta
Lenore Pereira, Takako Tabata, Matthew Petitt and June Fang-Hoover
During human pregnancy, HCMV spreads from the infected mother to the fetus, navigating the complex architecture of the human placenta, which anchors the fetus to the uterus. Primary sites of virus replication in the placenta include cytotrophoblast progenitor cells in chorionic villi and differentiating/invading cytotrophoblasts that breach uterine blood vessels and form a hybrid vasculature, increasing blood flow to the surface of the placenta. Focal virus replication and induction and release of paracrine factors result in pathology and a hypoxic intrauterine environment that stimulates compensatory development of vascularized floating villi. This chapter summarizes recent insights into the molecular changes that occur during virus replication, strategies to rescue development of the human placenta and the utility of placental villous explants and xenografts in SCID mice for quantifying infection in vitro and pathogenesis in vivo.

Chapter II.5 The Guinea Pig Model of Congenital Cytomegalovirus Infection
Alistair McGregor, Michael A. McVoy and Mark R. Schleiss
In the study of the cytomegaloviruses of small mammals, the guinea pig cytomegalovirus (GPCMV) has distinctive advantages. These attributes are chiefly related to the ability of GPCMV to cross the placenta, causing infection in utero. For this reason, the model is well-suited to the study of vaccines and antiviral drugs for preventing or modifying the outcome of congenital CMV infection, and for the study of the role of viral genes in the pathogenesis of maternal, placental and fetal infection. Progress in GPCMV studies has been hampered by a lack of detailed characterization of the viral genome and gene products, and a lack of immunologic reagents for animal study. However, recent efforts by several investigators have resulted in improved characterization of the GPCMV genome, and this information has in turn been applied to in vivo vaccine and pathogenesis studies. As is the case for human cytomegalovirus, the GPCMV glycoprotein B (gB) has proven to be a major target of humoral immune responses, and purified recombinant forms of gB have recently been shown to be effective vaccines in the guinea pig model. The study of viral genes has been facilitated by the availability of bacterial artificial chromosome (BAC) clones of the GPCMV genome in E. coli, which has enabled mutagenesis studies of the role of specific viral genes in pathogenesis and immunity. Insights from the ongoing characterization of the GPCMV model should prove germane to the understanding of the correlates of protective immunity for the fetus. The study of protective immunity in this model as well as potential viral determinants of pathogenesis could facilitate a better understanding of congenital HCMV disease, and may help inform and direct future HCMV intervention trials designed to protect the fetus from the disabling effects of this infection.

Chapter II.6 Murine Model of Neonatal Cytomegalovirus Infection
William J. Britt, Djurdjica Cekinović and Stipan Jonjić
Congenital HCMV infection of developing CNS is a major cause of long-term neuronal morbidity. Prevention of neurological damage due to CNS infection is considered as the primary goal of vaccine strategies and passively administered biologics. Due to species specificity of CMVs animal models have been developed in order to paradigmatically analyze the course of CMV infections. While different animal models provide good tools for studies of HCMV infections in the immunocompromised host, no single animal model completely recapitulates the pathogenesis of congenital HCMV infection. The murine model of perinatal MCMV infection in newborn mice has been proven as powerful tool to analyze the pathogenesis of congenital HCMV infection and mechanisms of the immune response which control CNS infection in the developing brain. This chapter describes a model of MCMV infection in neonatal mice that represents various aspects of HCMV infection in neonates, and thus, could be highly predictive for possible antiviral interventions in humans.

Chapter II.7 Adaptive Cellular Immunity to Human Cytomegalovirus
Mark R. Wills, Gavin M. Mason and J. G. Patrick Sissons
Primary HCMV infection induces robust CD8⁺ cytotoxic, and CD4⁺ helper, T cell mediated immune responses, which are associated with the resolution of acute primary infection: these responses are maintained at high frequency in long-term memory as the virus establishes persistent infection, with latency and periodic reactivation. Many of these T cells are specific for epitopes in the pp65 and IE1 HCMV proteins, but it is apparent that many other viral proteins can also be T cell targets, and in some individuals pp65 and IE1 responses are not immunodominant. During long-term carriage of the virus a balance is established between the T cell mediated immune response and viral reactivation: the T cell response controls viral spread following reactivation, but the virus encodes multiple genes that interfere with MHC-I antigen processing (US 2, 3, 6 and 11), and with MHC-II processing and NK cell killing, allowing limited viral evasion of the response. Loss of this balance is most evident in the immunocompromised host in whom reactivation of latent virus or primary infection can lead to unchecked viral replication, with consequent disease and mortality. This chapter describes current understanding of CD8⁺ and CD4⁺ T cell responses to HCMV, and how these responses reconstitute after bone marrow transplantation and might be used as therapies to protect against HCMV disease in immunocompromised subjects. The phenomenon of "memory T cell inflation" associated with HCMV and its relationship to immunosenesence is also discussed.

Chapter II.8 Natural Killer Cells and Human Cytomegalovirus
Gavin W. G. Wilkinson, Rebecca J. Aicheler and Eddie C. Y. Wang
The efficient downregulation of HLA-I by HCMV has the clear potential to render infected cells extremely vulnerable to NK cells. Moreover, the major IE genes activate cell responses that stimulate efficient transcription of multiple ligands for NK cell activating receptors. The capacity of HCMV to persist in vivo can clearly be ascribed to its ability to modulate NK cell responses. To date 7 functions encoded by HCMV have been formally demonstrated to suppress NK cell activation. UL18 is an MHC-I homologue that binds the inhibitory receptor LIR-1, while UL40 rescues expression of HLA-E, a ligand for the inhibitory receptor CD94-NKG2A. UL16, UL142 and miR-UL112 target multiple ligands for the ubiquitous NK activating receptor NKG2D, while UL141 targets ligands for the ubiquitous activating receptors DNAM-1 and TACTILE. The UL83-encoded major tegument protein (pp65) is unique in that it binds directly to inhibit the activating receptor NKp30. It is becoming evident that a substantial proportion of the remarkable coding capacity of this virus is directed at systematically addressing the NK cell response. Outwith the immediate goal of understanding HCMV pathogenesis, research on these immunodulatory functions are providing remarkable insights into the mechanisms that regulate human NK cell responses. Recent studies demonstrate that during its lifelong persistent/latent infection, HCMV induces dramatic changes in the NK cell repertoire leading specifically to expansions of NK cell subsets expressing CD94-NKG2C, LIR-1 and CD57. There is growing interest in these changes in the NK cell response as they potentially contribute to an emerging paradox: an 'adaptive' response by a supposedly innate arm of the immune system. This amplification of specific NK cell subsets to the virus may be instrumental in controlling infections, and may also be disrupted by immunosuppression. NK cells undoubtedly play a crucial role in controlling HCMV infections. There is a compelling need to understand the mechanisms by which HCMV evades, modulates, and ultimately is recognised by 'innate' defence systems.

Chapter II.9 Innate Immunity to Cytomegalovirus in the Murine Model
Silvia Vidal, Astrid Krmpotić, Michal Pyzik and Stipan Jonjić
Cells of the innate immune system, including macrophages, DCs and NK cells play an important role in the control of viral infection before the induction of a specific immune response, of which generation they are also crucial. The infection of mice with MCMV as a model of HCMV infection has been particularly informative in elucidating the role of innate and adaptive immune response mechanisms during infection. NK cells are considered the most important effector cells in early CMV surveillance. An evolutionary struggle between NK cells and CMVs can be inferred from the existence of a broad range of viral mechanisms designed to compromise NK-cell function. This chapter describes major innate immune response mechanisms involved in control of MCMV, with an emphasis on NK-cell mediated viral detection as well as virally-encoded immune evasion mechanisms.

Chapter II.10 Protective Humoral Immunity
Michael Mach, Anna-Katharina Wiegers, Nadja Spindler and Thomas Winkler
The generation of antibodies represents a powerful tool of the adaptive immune system in the battle against viral infections. Targets for antibodies with potential antiviral activity are glycoproteins in the viral envelope and/or on the surface of infected cells. In recent years, considerable progress has been made in our understanding of the protective antibody response against cytomegaloviruses. Animal studies have unambiguously demonstrated the protective capacity of antibodies both in prophylaxis as well as in therapy of existing primary infection or reactivation. A number of human monoclonal antibodies have been isolated which show potent virus-neutralizing capacity and new antibody targets have been identified. However, we still need to expand our knowledge on the mechanisms of virus neutralization by antibodies and the mode of action of protective antibodies in vivo. Increasing this knowledge will help us to rationally design strategies to limit the consequences of infections in populations at risk for CMV-disease.

Chapter II.11 Immunoregulatory Cytokine Networks Discovered and Characterized during Murine Cytomegalovirus Infections
Marc Dalod and Christine A. Biron
In addition to mediating early defense during primary infection, innate immunity delivers immunoregulatory functions to shape innate and adaptive immunity. Basic knowledge on the mechanisms inducing innate cytokine responses and the consequences for orchestrating downstream immunity is being advanced at a dramatic rate. Studies of murine cytomegalovirus (MCMV) infections in mice have contributed many of the breakthrough discoveries in these areas. Although intrinsic differences in viruses, hosts, and infection sites result in unique host-microbe relationships, there are overlapping effects mediated by host cell subsets and molecules. Thus, the information resulting from the leading-edge characterization of responses to MCMV has set the framework for understanding responses to a variety of infections in humans and mice and provided insights on approaches for enhancing resistance to virus-induced diseases. Key areas of progress include sensing of infection, co-ordination of cellular and innate cytokine cascades, consequences for delivery of innate and adaptive immunity to mediate defense, and regulation to protect from immune-mediated damage. These are reviewed here with a focus on the early cytokine/chemokine networks as infection spreads through a host. The surprisingly elegant picture emerging is one of profound flexibility for orchestrating optimal subset innate responses to protect against diverse and complex infectious organisms.

Chapter II.12 Host Genetic Models in Cytomegalovirus Immunology
Chris A. Benedict, Karine Crozat, Mariapia Degli-Esposti and Marc Dalod
Mouse cytomegalovirus (MCMV) was first isolated more than half a century ago (Smith, 1954). Subsequent studies of MCMV in its natural host have yielded enormous information regarding the cellular and molecular immune mechanisms that regulate the various phases of this lifelong β-herpesvirus infection. As the techniques and tools for studying mechanisms of immune defense in mice have advanced, so has our understanding of the specific host pathways that operate to control this complex host-pathogen relationship. In this chapter we will review how various mouse genetic models have defined an initial blueprint for how immune control of MCMV is achieved, both at the level of innate and adaptive immunity, and where we foresee the advancements in this model of CMV infection will come from in the future.

Chapter II.13 Clinical Cytomegalovirus Research: Thoracic Organ Transplantation
Robin K. Avery
Heart and lung transplantation can be lifesaving therapies for end-stage organ disease in some patients. Despite advances in antiviral prevention, cytomegalovirus infection is still an important issue in post-transplant management and may contribute to survival-limiting dysfunction of the transplanted organ. This chapter reviews the clinical presentations and risk factors for CMV infection in thoracic transplant recipients, as well as the direct and indirect effects of CMV. Recent studies on CMV-specific immunity and allograft dysfunction have shed further light on the differential benefits of prophylaxis and pre-emptive strategies for CMV prevention, as well as the potential benefits of an extended duration of prophylaxis. Finally, the development of newer anti-CMV agents holds promise for therapeutic management in the future.

Chapter II.14 Clinical Cytomegalovirus Research: Liver and Kidney Transplantation
Vincent C. Emery, Richard S.B. Milne and Paul D. Griffiths
CMV infection significantly impacts on the success of transplantation of abdominal organs. There are a range of both direct and indirect effects attributable to CMV. In this chapter we survey our current understanding of CMV pathogenesis, the immune control of CMV replication in these transplanted patients, the antiviral chemotherapeutic options available for managing infection/disease and consider the newer options available for drug therapy and for vaccination.

Chapter II.15 The Rat Model of Cytomegalovirus Infection and Vascular Disease
Sebastian Voigt, Jakob Ettinger and Daniel N. Streblow
Infection of rats with RCMV serves as an important model to study human CMV-related diseases. Two prototype RCMV isolates, the English isolate of RCMV (RCMV-E) and the Maastricht isolate (RCMV-M) have been described in the literature that differ significantly from each other by genome size, restriction fragment length polymorphism, and genome content. According to genome size, the RCMV-M genome is similar to that of murine CMV whereas RCMV-E has a substantially smaller genome consisting of only 203 kbp. In addition, RCMV-E encodes several genes that are not part of the other rodent CMV genomes, which makes it a distinct virus. In this chapter, we will first highlight these particular genes and their impact on the immune system as well as on recent advances in the understanding of RCMV biology. In the second part, we will focus on the use of RCMV-M in studying vascular disease.

Chapter II.16 Clinical Cytomegalovirus Research: Hematopoietic Cell Transplantation
Sachiko Seo and Michael Boeckh
HCMV infection remains an important complication after hematopoietic cell transplantation (HCT), although significant progress in the management of HCMV infection and disease has been made in the last two decades. A major achievement has been the optimization of preemptive therapy strategies based on surveillance by the pp65 antigenemia assay or HCMV DNA or RNA detection. However, current strategies are limited by the toxicity of antiviral agents and breakthrough disease in highly immunosuppressed individuals. Antiviral resistance occurs infrequently after HCT, but can be a considerable management challenge. This chapter outlines the current topics in host immunity, diagnosis, prevention, treatment of HCMV disease in HCT recipients, and future directions of HCMV management.

Chapter II.17 Murine Model for Cytoimmunotherapy of CMV Disease after Hematopoietic Cell Transplantation
Rafaela Holtappels, Stefan Ebert, Jürgen Podlech, Annette Fink, Verena Böhm, Niels A.W. Lemmermann, Kirsten Freitag, Angélique Renzaho, Doris Thomas and Matthias J. Reddehase
Cytomegalovirus (CMV) disease is a clinically relevant complication in hematopoietic (stem) cell transplantation (HCT). The murine model of CMV infection in the phase of hematopoietic reconstitution after experimental HCT has been pivotal in defining efficient endogenous reconstitution of donor (D)-derived antiviral CD8⁺ T cells as the decisive immune parameter for the control of lytic CMV replication and the prevention of acute manifestations of end-organ disease in HCT recipients (R). Endogenous reconstitution of protective immunity occurs with some delay, since hematopoietic stem cells and T-cell lineage lymphopoietic progenitors need to engraft in bone marrow (BM) stroma, migrate to the thymus for thymic self/non self T-cell receptor specificity selection, and emigrate as mature but naïve CD44^low T cells to the periphery where they encounter viral antigen to become 'primed', expand clonally, and differentiate into antiviral effector and memory cell subsets. These processes take time, and depending on when CMV reactivates in HCT recipients, endogenous reconstitution may come too late. In addition, the murine model has shown that CMV directly interferes with endogenous reconstitution by infecting BM stromal cells and inhibiting the expression of stromal cell-derived hemopoietins, specifically of stem cell factor (SCF). Depending on the precise conditions, BM pathogenesis of CMV, often referred to as 'myelosuppression', can range from reduced engraftment to a complete graft failure resulting in BM aplasia. Substituting HCT with already primed, 'ready-to-go' CMV-specific CD8⁺ effector and/or memory T cells, also known as 'adoptive T-cell transfer' or 'preemptive cytoimmunotherapy', can provide immediate protection. Key parameters of protection by CD8⁺ T cells were revealed by the murine model: (i) memory cell subsets isolated ex vivo from immune donors are ~ 100-fold more efficient than cell culture-propagated short-term cytolytic effector cell lines of identical specificity, (ii) the magnitude of the primary immune response to a viral epitope, its 'immunodominance', does not correlate with protection mediated by cognate T cells; (iii) viral immune evasion proteins determine if an epitope is 'protective', and (iv) genetic deletion of dominant protective epitopes in either the donor's or the recipient's virus has little impact on protection by a broadly-specific T-cell population, predicting 'robustness' of T-cell immunotherapy towards antigenic variation in virus strains or clinical isolates.

Chapter II.18 State of the Art and Trends in Cytomegalovirus Diagnostics
Maria Grazia Revello and Giuseppe Gerna
Diagnosis of human cytomegalovirus (HCMV) infection is required in two clinical situations: the immunocompetent HCMV-seronegative pregnant woman, and the immunocompromised patient. In the case of pregnant women, diagnosis is primarily based on serology, but also on detection of viral DNA in blood. Viral DNA in blood may be quantified by the following assays: viremia (infectious virus in blood), antigenemia (leukocytes carrying virus or viral products) or DNAemia. In pregnant women diagnosis of primary infection is mandatory, in view of the possible virus transmission to the fetus. In the fetus, virus infection is diagnosed by performing viral assays on amniotic fluid and, when appropriate, on fetal blood. In newborns, diagnosis of congenital infection may be achieved by virus detection at birth. In immunocompromised transplanted patients virus quantification in blood is also mandatory to determine optimal time to intervene by antiviral treatment, unless a prophylaxis approach is adopted. Repeated antiviral drug courses may cause emergence of drug-resistant HCMV strains harbouring mutations in the UL97 or UL54 genes. Control of HCMV infection is guided by the immune response, which is elicited by viral infection at the level of both humoral and T-cell immunity.

Chapter II.19 Antiviral Therapy, Drug Resistance, and Computed Resistance Profiling
Detlef Michel, Meike Chevillotte and Thomas Mertens
Three drugs are currently used for treatment of human cytomegalovirus (HCMV) disease or infection: ganciclovir (GCV)/valganciclovir (valGCV), cidofovir (CDV), and foscarnet (FOS). They all target the viral DNA polymerase pUL54, thereby inhibiting viral DNA replication. In contrast to antiviral treatment of overt HCMV disease, antiviral prophylaxis and pre-emptive therapy aim at prevention of HCMV disease. All current anti-HCMV compounds cause drug-specific and severe side effects and have been reported to select for clinically relevant drug resistant virus variants. Active systemic HCMV infection can be first asymptomatic or symptoms can be non-specific. Therefore, a reliable and fast diagnosis of active systemic viral infection is needed, based on virological markers. This includes early and quantitative detection of drug resistant HCMV variants. Genotyping will become the method of choice for identification of viral drug resistance, but absolutely requires previous quantitative characterization of the effect of individual and combined mutations on the resistance phenotype. A database has been made available in the www containing all published mutations and according information on the quantitative resistance phenotypes. In view of the many published resistance mutations, the database is a helpful tool to correlate diagnosed mutations in a viral genome with resistance. New compounds to treat HCMV infection and disease are urgently needed. They should ideally combine few adverse effects, good oral bioavailability, the option to treat children in utero, as well as novel mechanisms of action, to possibly reduce selection of resistant virus variants by combination therapy. Some substances should also target early steps of viral infection, thereby inhibiting IE- and E-gene expression in infected cells. Modified and new nucleoside analogues, small-molecule compounds, benzimidazoles, indolocarbazole protein kinase inhibitors as well as drugs with originally other indications (leflunomide, artesunate) will soon augment the HCMV antiviral portfolio. They will expand treatment options, but will also increase the number of resistance-conferring mutations, thereby rendering resistance analyses even more complex.

Chapter II.20 Cytomegalovirus Vaccine: On the Way to the Future?
Stanley A. Plotkin and Bodo Plachter
Prenatal transmission of CMV is a frequent cause of mental retardation and hearing loss in children. Furthermore, infection with this virus is a severe threat to immunocompromised patients. Consequently, development of a vaccine to prevent CMV disease has been identified as a first rank medical priority. Goals and target populations for such a vaccine have been identified. Antigens to be targeted by vaccine-induced immune responses have been defined indicating that only a subset of the more than 150 viral proteins may be sufficient to induce protective immunity. Using this information, strategies for the development of live virus vaccines as well as subunit vaccines have been developed. At this point at least seven candidate vaccines have been tested clinically and many other approaches are being explored.

Chapter II.21 Vaccine Vectors Using the Unique Biology and Immunology of Cytomegalovirus
Michael A. Jarvis, Scott G. Hansen, Jay A. Nelson, Louis J. Picker and Klaus Früh
Cytomegaloviruses (CMVs) have a unique immunobiological relationship with their mammalian hosts in which low level persistent infection and/or frequent low level reactivation of latent infection results in the development and life-time maintenance of high frequency, effector memory T cell (T_EM) responses that are characterized by the continuous presence of fully differentiated anti-viral T cells in the periphery of the infected host. This unique immunology has recently been exploited to develop vaccine vectors that are distinguished from other viral vectors in their ability to elicit and maintain T cells with similar T_EM-biased characteristics that are directed against heterologous foreign pathogens. Such responses would be predicted to intercept and control/eliminate such pathogens early in infection (without needing an anamnestic response) prior to full implementation of the pathogen's own immune evasion strategies. In non-human primate models of AIDS such T_EM-inducing rhesus CMV (RhCMV) vectors were able to completely control highly pathogenic, mucosally administered SIV infection prior to systemic spread, a pattern of protection that has not been observed with conventional T cell vaccines. An additional feature that makes CMV particularly suited for use as a vaccine vector is its ability to superinfect and then persist in the healthy CMV immune (CMV-seropositive) host. This remarkable characteristic has enabled use of this vaccine platform regardless of the CMV status of the vaccine recipient. Superinfection, defined as the establishment and maintenance of a secondary infection in an infected (and therefore 'immune') host, requires evasion of pre-existing CMV-specific T cells. A final distinguishing feature of CMV vectors is the surprising finding that viral latency and persistent immune stimulation does not require spread of the vector beyond the initial infected host cell. The long-term immune stimulatory capacity of such 'spread-deficient' CMVs suggests that CMV-based vectors can be rendered safe whilst maintaining T_EM responses to the heterologous target antigen. T_EM-inducing CMV vectors have the potential to be useful against many infectious diseases as well as cancer in diverse human and animal populations.

Chapter II.22 Non-Human-Primate Models of Cytomegalovirus Infection, Prevention, and Therapy
Klaus Früh, Daniel Malouli, Kristie L. Oxford and Peter A. Barry
The last few years have witnessed significant expansion of the Non-Human-Primate (NHP) models of CMV persistence and pathogenesis. Progress in the utilization of the NHP CMV models has been highlighted by a better understanding of natural history, comparative genomic sequence analyses, and in vivo studies addressing mechanisms of tissue tropism, immune modulation, vaccine development, and optimization of the use of CMV as a vaccine vector for ectopic expression of heterologous antigens. The earliest observations of CMV infection in NHP during the first part of the twentieth century were remarkable for their prescient descriptions of CMV-host relationships based entirely on microscopic characterization of the protozoan-like (cytomegalic) cells that had been noted in congenitally infected human infants (Ribbert, 1904; Goodpasture and Talbot, 1921) and guinea pigs (Jackson, 1920). In particular, it was noted in the 1920's and 1930's that NHP CMV (1) is a ubiquitous infectious agent, (2) infects multiple cell types, (3) is characterized by low virulence, and (4) modifies host inflammatory responses. In addition, the first use of the term "latency" to describe the ability of CMV to reactivate may have been used for NHP CMV. In 1935, Cowdry and Scott recognized that treatment of CMV-infected monkeys with irradiated ergosterol stimulated reactivation of CMV in multiple tissues, and they noted that the treatment "may have activated or intensified a process already latent in the kidneys" (Cowdry and Scott, 1935). The recent progress in the NHP models follows these earliest insights into the hallmarks of CMV infections, and now enables the unique positioning of NHP models to provide a better understanding, treatment, and prevention of HCMV infection and disease in humans. This chapter summarizes the current status of our understanding of NHP CMVs with particular emphasis on viral gene function and viral disease models.

Chapter II.23 Putative Disease Associations with Cytomegalovirus: a Critical Survey
Ann B. Hill
In recent years it has been suggested that CMV may be involved in the pathogenesis of a variety of conditions in which there may not be clear evidence of viral replication. These "non-traditional" disease associations include glioblastoma and various other cancers, atherosclerotic cardiovascular disease, Alzheimer's disease, and immunosenescence, amongst others. The pathologies fall into two broad groups: tumors, and inflammatory diseases of aging. In the case of tumors, some groups have used ultrasensitive detection techniques and report finding CMV in the majority of tumor cells. In the case of inflammatory diseases of aging, the evidence mostly comes from epidemiological studies that have associated CMV serology or CMV-driven alterations in T cell populations with various outcomes. While CMV's biology provides ready explanations for these putative disease associations, the actual evidence for its being involved remains controversial. This chapter will review the evidence for several putative disease associations.

Résumé Résumé and Visions: From CMV Today to CMV Tomorrow
Ulrich H. Koszinowski
There is no Abstract Section so we provide the opening two paragraphs for the Résumé instead: This new book on cytomegalovirus is both a timely update and an extension of the previous book, now giving more room also to clinical observations and studies. '... and what is the use of a book,' thought Alice, 'without pictures or conversation?' (Lewis Carroll, Alice in Wonderland). This book is written by a selected trustworthy group of world-renowned virologists ... and, yes, it has great pictures! It is the inevitable fate of all published scientific observations from a given period to be digested and to end up as a state-of-the-art review book. The digest is made for us by other experts and we are usually more than happy to trust their work. The book gives us the advantage to memorize less than we used to or had to. We can just look it up. Such a collection of reviews must be counted according to Orwell's definition among 'the best books ... those that tell you what you know already.'

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