Epstein-Barr Virus: Latency and Transformation
"packed with valuable information" (Doodys)
Caister Academic Press
Erle S. Robertson
Tumor Virology Program, Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, PA 19104-6076, USA
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Epstein-Barr virus (EBV) is a human gamma herpes virus that is best known for being the causative agent of infectious mononucleosis in man. A fascinating feature of this virus is its ability to persist in the host and it is estimated that more than 95% of adults are carriers of the virus. Importantly, EBV can transform latently infected primary cells from healthy individuals into cancerous ones, thereby causing important human cancers such as B-cell neoplasms (e.g. Burkitt's lymphoma and Post-transplant lymphomas), certain forms of T-cell lymphoma, and some epithelial tumours (e.g. gastric carcinomas). Understanding viral latency, what triggers viral reactivation and the mechanism of transformation of normal host cells into malignant cells are critical for the development of strategies for the prevention and control of this intriguing virus and related cancers.
In this book, expert EBV virologists comprehensively review this important subject from a genetic, biochemical, immunological, and cell biological perspective. Topics include: latent infections, EBV leader protein, EBNA-1 in viral DNA replication and persistence, EBNA-2 in transcription activation of viral and cellular genes, the nuclear antigen family 3 in regulation of cellular processes, molecular profiles of EBV latently infected cells, latent membrane protein 1 oncoprotein, regulation of latency by LMP2A, role of noncoding RNAs in EBV-induced cell growth and transformation and the regulation of EBV latency by viral lytic proteins. This book is essential reading for all EBV virologists as well as clinical and basic scientists working on oncogenic viruses.
"the latest research and information on the mechanisms used by latent EBV to transform host cells ... a comprehensive review of the vast amount of information that is currently available ... a good book for scientists ... packed with valuable information" from Doodys
Table of contents
1. Latent Epstein-Barr Virus Infections
Elliott Kieff, Eric Johannsen, and Michael Calderwood
In primary infection, Epstein-Barr Virus (EBV) replicates in oro-pharyngeal epithelial cells and establishes Latency III, II, and I infections in B-lymphocytes. EBV latent infection of B-lymphocytes is necessary for virus persistence, subsequent replication in epithelial cells, and release of infectious virus into saliva. EBV Latency III and II infections of B-lymphocytes, Latency II infection of oral epithelial cells, and Latency II infection of NK- or T-cell can result in malignancies, marked by uniform EBV genome presence and gene expression. Because of the marked CD4+ and CD8+ T-cell response to EBV nuclear proteins in Latency III infected B-lymphocytes, EBV associated lymphoid malignancies are most common in immune compromised people, whereas EBV associated Latency II infected anaplastic Nasopharyngeal Carcinoma is not more common in immune compromised people and is most common in otherwise normal Southestern Chinese people. This introduction highlights key aspects of what has been learned over the past 45 years about the role of EBV Latent infection associated gene expression in maintaining EBV episomes in dividing cells and in increasing cell growth and survival. We expect that a clear view of the current picture and access to more detailed references can be useful for applying new experimental approaches. The ensuing chapters are intended to fulfill those missions.
2. Epstein-Barr Virus Leader Protein
Paul D. Ling
Epstein-Barr virus (EBV) efficiently infects and immortalizes human B lymphocytes through expression of at least 12 viral genes, which include the EBNA-LP protein. This chapter will cover the current state of knowledge about how EBNA-LP contributes to EBV biology. EBNA-LP is an enigmatic protein comprised largely of 22 and 44 amino acid repeated sequences. Elucidation of EBNA-LP functions has been guided by identification of interacting cellular and viral proteins. The functions of these cofactors implicate EBNA-LP as a potential modulator of apoptosis, cell cycle processes, and transcriptional pathways. Recent studies have linked EBNA-LP with Sp100, a protein associated with promyelocytic nuclear body proteins (PML NBs), which mediate intrinsic cellular defenses against viral infections. Alpha and beta herpesviruses encode proteins, which interact with and modulate PML NBs or PML NB-associated proteins to counteract this intrinsic cellular defense. These results link EBNA-LP with pathways that counteract or modulate the intrinsic host defense mechanisms.
3. EBNA1 in Viral DNA Replication and Persistence
EBNA1 is the latent origin binding protein of Epstein-Barr virus and the only viral protein needed for the replication and stable persistence of EBV episomes. The contributions of EBNA1 include facilitating the initiation of DNA synthesis and ensuring the even distribution of the viral episomes to daughter cells during mitosis, a function that involves tethering the episomes to the cellular chromosomes. EBNA1 also activates the transcription of other viral latency genes important for cell immortalization and can autoregulate its own expression. In addition, EBNA1 has been found to alter the cellular environment in a number of ways consistent with a direct contribution to cell immortalization and malignant transformation. This chapter discusses all of the known functions of EBNA1 and the mechanisms by which they occur.
4. EBNA-2 in Transcription Activation of Viral and Cellular Genes
Epstein-Barr virus nuclear antigen-2 (EBNA-2) plays a key role in B-cell growth transformation by initiating and maintaining the proliferation of infected B-cells upon EBV infection in vitro. EBNA-2 is one of the first viral genes expressed after virus infection. By activating viral as well as cellular target genes EBNA-2 initiates the transcription of a cascade of primary and secondary target genes, which eventually govern the activation of the resting B-cell, cell cycle entry and proliferation of the growth transformed cells. The growth transformed B-cells exhibit a phenotype reminiscent of antigen activated B-cells. In addition, EBNA-2's anti-apoptotic activities protect the infected B-cell. The multiple mechanisms by which EBNA-2 exerts its function are reflected by the association of EBNA-2 with several cellular and viral proteins as well as a rapidly growing spectrum of activated cellular target genes. The finding that EBNA-2 and activated Notch signalling both converge on the cellular DNA binding and repressor protein CBF1 has raised the question, to which extent the functions of both proteins overlap.
5. Epstein-Barr Virus Nuclear Antigen Family 3 in Regulation of Cellular Processes
Karen Sims, Abhik Saha, and Erle S. Robertson
Epstein-Barr virus (EBV) infects over 90% of the world's population, and like other herpesviruses it establishes a permanent latent infection in the host (Rickinson and Kieff, 2002). The native B-lymphocyte is the preferred target of EBV, which after differentiation into memory B-cells contains the latent reservoir of virus subsequent to the resolution of acute infection. Several malignancies have been associated with EBV infection, including nasopharyngeal carcinoma, endemic Burkitt's lymphoma, AIDS-related lymphoma and post-transplant lymphoproliferative disorder, among others (Rickinson and Kieff, 2002). During the latent phase of infection and in EBV-associated tumors, a limited number of viral proteins are expressed, among them the Epstein-Barr nuclear antigen 3 (EBNA3) family of proteins. Of these three proteins, two (EBNA3A and 3C) are absolutely indispensable for viral transformation of B-lymphocytes, and all appear to significantly contribute to maintaining the viability of transformed cells, suggesting an important role in oncogenesis (Kieff and Rickinson, 2002). These viral proteins interact with numerous cellular factors, including transcriptional regulators, cell-cycle components and cytoskeletal elements. Additionally, the EBNA3 family of proteins appears to regulate the expression of other crucial viral proteins and modulate their functions, creating an intricate system of checks and balances critical for lifelong survival of the virus in the host.
6. Molecular Profiles of EBV Latently Infected Cells
Michael A Calderwood and Eric C. Johannsen
EBV immortalizes B lymphocytes through the expression of latent genes encoding the membrane proteins (LMPs) and nuclear proteins (EBNAs). LMPs and EBNAs profoundly impact the B cell through usurping cell signaling cascades required for B cell survival and growth. Modulation of the NF-κB, B cell receptor, Notch, and possibly other signaling pathways permits a substantial reprogramming of the EBV infected cell with a limited gene repertoire. Molecular profiling of mRNAs induced and repressed by EBV infection of cells has consistently revealed extensive changes in gene expression, but there is remarkably little concordance among different studies. The most consistently EBV induced genes are downstream of LMP1 and EBNA2 and most of the attributable EBV repressed genes are due to EBNA2. The apparent dominance of EBNA2 and LMP1 in EBV gene regulation may be partly attributable to the emphasis on genes experiencing the most extreme fold changes in expression. Future mRNA profiling studies using common platforms for analysis may permit identification of more subtle effects on gene expression and elucidate the role(s) played by the other EBV latency gene products.
7. The EBV Latent Membrane Protein 1 Oncoprotein
Kenneth M. Izumi
Latent infection membrane protein 1 (LMP1) is expressed in most malignances associated with EBV infection, has oncogene-like effects on immortalized fibroblasts, and is essential for EBV to efficiently transform the growth of resting primary B-lymphocytes into long-term autonomously proliferating lymphoblastoid cell lines. Recombinant virus, genetic, and biochemical analyses have revealed that LMP1 is a constitutively active membrane receptor that appropriates signaling adapters of the tumor necrosis factor receptor superfamily to alter cell gene expression through NF κB, mitogen-activated protein kinases, or interferon regulatory factors. LMP1 signaling mediated alterations in gene expression are critical for long-term cell proliferation and survival, and this is consistent with a significant role in the development of malignancies in vivo. Thus, there is considerable effort in clarifying the molecular mechanisms of LMP1 signaling and their effects on cell growth, survival and gene expression as a critical step in identifying targets for interventions to specifically prevent or treat EBV-related cancers, particularly in the context of immune suppression.
8. Regulation of EBV Latency by LMP2A
Kathryn T. Bieging, Leah J. Anderson, and Richard Longnecker
Latent membrane protein 2A (LMP2A) is expressed in cells latently infected with EBV, as well as in many of the pathologies that are associated with EBV infection. The consistent detection of LMP2A in various EBV-associated malignancies and latency programs point to the essential role that this protein plays both in the viral life cycle and in disease manifestations. Detailed analysis of LMP2A function has uncovered dramatic effects on B cell biology. LMP2A has been described as a B cell receptor (BCR) signaling mimic, inducing signaling cascades that inhibit apoptosis and promote cell survival. LMP2A also has dramatic effects on development and differentiation as evidenced by transgenic mouse phenotypes and analysis of transcriptional profiles. The molecular bases for these functions of LMP2A underlie its contribution to development of various epithelial and lymphoid malignancies including nasopharyngeal carcinoma and Hodgkin's Lymphoma, and help to explain the role of LMP2A in the EBV life cycle and maintenance of viral latency.
9. The Role of Noncoding RNAs in EBV-induced Cell Growth and Transformation
Epstein-Barr virus (EBV) expresses two small RNAs known as EBERs (EBV-encoded RNAs) and several microRNAs. EBERs are the most abundant viral transcript produced during latent infection by EBV in a wide variety of cell types and disease conditions. They have been demonstrated to have a variety of effects on cell growth and physiology in experiments performed in vitro and in cell culture remains to be defined. Although the abundance of EBERs in latently infected cells implies an important function, their biological role in vivo and their molecular mechanisms of action remain poorly understood. The current state of knowledge with respect to the regulation of EBER expression, their structure, their interactions with cellular proteins and their roles in protecting EBV mediated cell transformation is presented and the controversies regarding EBER functions are discussed. EBV microRNAs function in regulating both EBV genes and cellular genes. Expression of EBV miRNAs is dependent on a variety of factors, including the host cell type. The potential roles of EBV miRNAs in oncogenesis, immune mechanisms and gene regulation are presented.
10. Regulation of EBV Latency by Viral Lytic Proteins
Zhen Lin and Erik K. Flemington
Similar to other herpesviruses, EBV exhibits a biphasic life cycle involving a replicative phase and a latency phase. Following initial infection, EBV preferentially exists in host cells in a state of "latency" in which no viral production occurs. Upon receiving certain activation signals, latency can be disrupted and entry into the productive replicative stage of the life cycle ensues. Following the initial triggering of the lytic cycle, progression of the lytic cascade is manifested by the expression of the viral immediate-early (IE) and early viral regulatory proteins, Zta, Rta, and Mta. In this chapter, we will focus on the biological roles of these key EBV lytic cycle regulators and we will discuss the interplay between the lytic and latent phases of the EBV life cycle.
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(EAN: 9781904455622 9781912530809 Subjects: [virology] [microbiology] [medical microbiology] )