Herpesvirus Latency

This comprehensive account of the human herpesviruses provides an encyclopedic overview of their basic virology and clinical manifestations. This group of viruses includes human simplex type 1 and 2, Epstein–Barr virus, Kaposi's Sarcoma-associated herpesvirus, cytomegalovirus, HHV6A, 6B and 7, and varicella-zoster virus. The viral diseases and cancers they cause are significant and often recurrent. Their prevalence in the developed world accounts for a major burden of disease, and as a result there is a great deal of research into the pathophysiology of infection and immunobiology. Another important area covered within this volume concerns antiviral therapy and the development of vaccines. All these aspects are covered in depth, both scientifically and in terms of clinical guidelines for patient care. The text is illustrated generously throughout and is fully referenced to the latest research and developments.

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This volume provides an overview of the latency strategies developed during the estimated 200,000 year-long coevolution of Alpha-, Beta- and Gammaherpesvirinae and their host species. While the main emphasis is on herpesviruses infecting humans, relevant cases if herpesviruses infecting animals are covered as well. Special emphasis is given to results on molecular mechanisms regulating latent promoters of herpesvirus genomes and signals and molecular pathways resulting in reactivation of latent viral genomes.

The Epstein-Barr virus was discovered 15 years ago. Since that time an immense body of information has been accumu lated on this agent which has come to assume great signifi cance in many different fields of biological science. Thus, the virus has very special relevance in human medicine and oncology, in tumor virology, in immunology, and in mole cular virology, since it is the cause of infectious mononu cleosis and also the first human cancer virus, etiologically related to endemic Burkitt's lymphoma and probably to nasopharyngeal carcinoma. In addition, continuous human lymphoid cell lines initiated and maintained by the transform ing function of the virus genome provide a laboratory tool with wide and ever-growing applications. Innumerable papers on the Epstein-Barr virus have ap peared over recent years and reports of work with this agent now constitute a veritable flood. The present book provides the first and only comprehensive, authoritative over-view of all aspects of the virus by authors who have been the original and major contributors in their particular disciplines. A complete and up-to-date survey of this unique and important agent is thus provided which should be of great interest to experts, teachers, and students engaged in cancer research, virology, immunology, molecular biology, epide miology, and cell culture. Where topics have been dealt with from more than one of these viewpoints, some inevitable overlap and duplication has resulted; although this has been kept to a minimum, it has been retained in some places because of positive usefulness.

Persistent Viral Infections Edited by Rafi Ahmed Emory Vaccine Center, Atlanta, USA and Irvin S. Y. Chen UCLA School of Medicine, Los Angeles, USA During the past decade much of our attention has focused on diseases associated with viral persistence. Major breakthroughs in immunology, and the advent of molecular approaches to study pathogenesis have increased our understanding of the complex virus-host interactions that occur during viral persistence. Persistent Viral Infections focuses on: * The pathogenesis and immunology of chronic infections * Animal models that provide, or have the potential to provide, major insights This volume will be essential reading for virologists, immunologists, oncologists and neurologists.

DNA Methylation and Complex Human Disease reviews the possibilities of methyl-group-based epigenetic biomarkers of major diseases, tailored epigenetic therapies, and the future uses of high-throughput methylome technologies. This volume includes many pertinent advances in disease-bearing research, including obesity, type II diabetes, schizophrenia, and autoimmunity. DNA methylation is also discussed as a plasma and serum test for non-invasive screening, diagnostic and prognostic tests, as compared to biopsy-driven gene expression analysis, factors which have led to the use of DNA methylation as a potential tool for determining cancer risk, and diagnosis between benign and malignant disease. Therapies are at the heart of this volume and the possibilities of DNA demethylation. In cancer, unlike genetic mutations, DNA methylation and histone modifications are reversible and thus have shown great potential in the race for effective treatments. In addition, the authors present the importance of high-throughput methylome analysis, not only in cancer, but also in non-neoplastic diseases such as rheumatoid arthritis. Discusses breaking biomarker research in major disease families of current health concern and research interest, including obesity, type II diabetes, schizophrenia, and autoimmunity Summarizes advances not only relevant to cancer, but also in non-neoplastic disease, currently an emerging field Describes wholly new concepts, including the linking of metabolic pathways with epigenetics Provides translational researchers with the knowledge of both basic research and clinic applications of DNA methylation in human diseases

This volume has gathered some of the experts in the field to review aspects of our understanding of CMV and to offer perspectives of the current problems associated with CMV. The editors and authors hope that the chapters will lead to a better understanding of the virus that will assist in the development of new and unique antivirals, a protective vaccine, and a full understanding of CMV's involvement in human disease.

Cyprinid herpesvirus 3 (CyHV-3), commonly known as koi herpesvirus (KHV), is a member of the Alloherpesviridae and is a deadly pathogen for koi and common carp, Cyprinus carpio. It causes severe gill necrosis and nephritis, dermal ulceration and hemorrhage, and mass mortality of up to 100% of affected fish. Fish that survive KHV infection are latently infected lifelong carriers. Latency is a conserved mechanism among known herpesviruses and is under the control, in part, of viral gene and protein expression. Our previous study demonstrated that KHV becomes latent in peripheral white blood cells (WBC) of koi. In this study, KHV latency was further investigated in IgM WBC. The presence of the KHV genome in IgM WBC was about 20-fold more abundant than in IgM-WBC. To determine if KHV expressed genes during latency, transcription from all 8 open reading frames (ORFs) in the terminal repeat was investigated in IgM WBC from koi with latent KHV infection. Only a spliced ORF6 was found to be abundantly expressed in IgM+ WBC from KHV latently infected koi. The spliced ORF6 transcript was also detected in vitro during productive infection as early as 1 day post-infection. The ORF6 transcript from in vitro infection begins -127 bp upstream of the ATG and ends +188 bp downstream of the stop codon, +20 bp downstream of the polyadenylation signal. The hypothetical protein of ORF6 contains a consensus sequence with homology to a conserved domain of EBNA-3B and ICP4 from Epstein Barr virus and herpes simplex virus 1, respectively and both members of the Herpesviridae. This is the first report of latent KHV in B cells and identification of gene transcription during latency for a member of the Alloherpesviridae. To identify and collect an enriched population of KHV+ latently infected cells, a nanoflare probe was generated specific to ORF6 RNA and used to separate live KHV latently infected cells from total peripheral white blood cells. Using the nanoflare ORF6 probe, about 1% of peripheral WBC from latently infected koi were identified and collected by their expression of ORF6. When this enriched population of KHV+ latently infected cells was examined by RNA-seq, the ORF6 transcript was found to be the only viral transcript that consistently mapped to the KHV reference genome. This study demonstrated that a nanoflare RNA probe could be used to enrich latently infected cells, which can subsequently be used to characterize gene expression during KHV latency. Little is known about the molecular mechanisms and control of latency for KHV. In this study, the expression of viral protein from ORF6 mRNA was investigated by a polyclonal antibody specific to a synthetic peptide derived from predicted ORF6 protein (anti-ORF6). Using an immunofluorescence assay (IFA), positive staining to the anti-ORF6 was observed in both KHV-infected common carp brain (CCB) cells in vitro and IgM+ B cells from koi latently infected with KHV. No IFA staining was observed in uninfected CCB cells nor from IgM-B cells from KHV+ latently infected koi. The ORF6 protein expressed during productive infection was detected around 140 kDa, which is bigger than the ~80 kDa predicted protein. ORF6 protein at a similar size as the predicted protein was identified from cloned ORF6 protein in an expression vector pet6XHN transformed in E. coli. Based on an analysis using software GPS-SUMO, 5 potential sumoylation sites were identified in the ORF6 protein sequence. This study demonstrated that ORF6 protein is expressed during KHV latency in koi and may be sumoylated in infected cells. These works have unveiled molecular strategies of herpesvirus latency for KHV; the identification of a latency associated transcript as well as viral protein expression during latency, which demonstrate conserved mechanisms as other herpesvirus latency programs. Through these discoveries, it is possible to further investigate the conserved biology of herpesvirus latent infections by using the koi and KHV model for human herpesvirus associated diseases and therapies.

This is the story of the discovery of the first human cancer virus. Through intriguing accounts that include some remarkable characters and individual stories from around the globe - including the UK, Africa, USA, and China - it tells the story of the Epstein-Barr virus and the understanding of its connections to a variety of other diseases.

A great truth is a truth whose opposite. is also a great truth. Thomas Mann (Essay on Freud, 1937) This volume centers on pseudorabies (PR V), herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), and human cytomegalovirus (CMV) and fulfills three objectives. The chapters on the epidemiology and latency of HSV, and on the glycoproteins specified by HSV and CMV, set the stage for the discussions of the immunobiology and pathogenesis of human herpesvirus infections in Volume 4. The epidemiology of HSV is the basis of our understanding of the spread and survival of this virus in the human populations. Central to the epidemiology of HSV and its pathogenesis in humans is the ability of the virus to remain in a latent state for the life of its host. The viral membrane glycoproteins are among the most interesting virion proteins, primarily because of their critical role in the initiation of infection. Since they are the surface membrane proteins of the virion and appear on the surface of productively infected cells, they are also the obvious if not the exclusive targets of the immune response. The chapters on the transforming potential of HSV and CMV, and on the role of HSV in human cancer, deal with challenging problems requiring rather different experimental tools.