TY - BOOK AB - Nearly two decades after the discovery of Epstein-Barr virus (EBV), the latent membrane protein 1 (LMP1) was identified and recognized as the primary transforming gene product of the virus. LMP1 is expressed in most EBV-associated lymphoproliferative diseases and malignancies, where it plays a central role in pathogenesis. Over 40 years of research have established LMP1 as a potent driver of cellular transformation and survival, deregulating key signaling pathways, cellular metabolism, and transcription while simultaneously subverting programmed cell death mechanisms. Beyond its role in transformation and immortalization, LMP1 exerts multifaceted biological activities supporting tumorigenesis, including immune modulation, regulation of the tumor microenvironment, and promotion of migration and invasive tumor growth. Functioning as a constitutively active receptor that mimics co-stimulatory CD40 receptor signals in B-lymphocytes, LMP1 recruits cellular signaling molecules associated with tumor necrosis factor receptors (TNFRs), such as TNFR-associated factors (TRAFs) and the TNFR-associated death domain protein (TRADD). It triggers phosphorylation, ubiquitination, and SUMOylation events in the target cell to activate NF-κB, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), interferon regulatory factor (IRF), and STAT pathways. This review provides an updated and comprehensive overview of the biological and molecular functions of LMP1, highlighting its role as a critical interface in virus-host interactions and its potential as a therapeutic target. AU - Kieser, A. C1 - 75314 C2 - 58271 TI - The latent membrane protein 1 (LMP1): Biological functions and molecular mechanisms. JO - Curr. Top. Microbiol. Immunol. PY - 2025 SN - 0070-217x ER - TY - BOOK AB - Epstein-Barr virus (EBV) infection has been associated with an expanding range of acute inflammatory, malignant, and autoimmune disorders. Seroepidemiological studies, facilitated by the early identification of key immunodominant targets of the EBV-specific humoral response, have provided invaluable insights into pathogenicity and global prevalence and incidence of EBV infections. These studies have also identified distinct antibody signatures associated with both the acute and persistent phases of infection, as well as EBV-related disorders. Over time, research into the humoral immune response against EBV has progressed from traditional cell-based immunofluorescence methods to high-throughput multiplex assays utilizing recombinant proteins or synthetic peptides as substrates. These improvements have shifted the focus from individual immunodominant antigens to the entire EBV proteome, enhancing our understanding of antiviral antibody responses in both health and disease. Detailed analyses of antigenic epitopes have uncovered significant biochemical and sequence homology between viral and host proteins, providing a conceptual framework for understanding the development of autoimmune diseases by a phenomenon known as antigenic mimicry. Recently, research has shifted toward translating these immune response findings into therapeutic strategies aimed at inducing or restoring immunity in patients with EBV-associated disorders. This chapter seeks to provide a comprehensive overview of the humoral immune response to EBV in healthy virus carriers and patients with EBV-associated disorders, tracing developments from the discovery of the virus 60 years ago to the present day and offering a perspective on future directions. AU - Mautner, J. AU - Middeldorp, J.M.* C1 - 74905 C2 - 57714 TI - Epstein-Barr Virus (EBV)-Specific Humoral Immune Responses in Health and Disease. JO - Curr. Top. Microbiol. Immunol. PY - 2025 SN - 0070-217x ER - TY - JOUR AB - The Epstein–Barr virus is etiologically linked with the development of benign and malignant diseases, characterized by their diversity and a heterogeneous geographic distribution across the world. The virus possesses a 170- kb-large genome that encodes for multiple proteins and non-coding RNAs. Early on there have been numerous attempts to link particular diseases with particular EBV strains, or at least with viral genetic polymorphisms. This has given rise to a wealth of information whose value has been difficult to evaluate for at least four reasons. First, most studies have looked only at one particular gene and missed the global picture. Second, they usually have not studied sufficient numbers of diseased and control cases to reach robust statistical significance. Third, the functional significance of most polymorphisms has remained unclear, although there are exceptions such as the 30-bp deletion in LMP1. Fourth, different biological properties of the virus do not necessarily equate with a different pathogenicity. This was best illustrated by the type 1 and type 2 viruses that markedly differ in terms of their transformation abilities, yet do not seem to cause different diseases. Reciprocally, environmental and genetic factors in the host are likely to influence the outcome of infections with the same virus type. However, with recent developments in recombinant virus technology and in the availability of high throughput sequencing, the tide is now turning. The availability of 23 complete or nearly complete genomes has led to the recognition of viral subtypes, some of which possess nearly identical genotypes. Furthermore, there is growing evidence that some genetic polymorphisms among EBV strains markedly influence the biological and clinical behavior of the virus. Some virus strains are endowed with biological properties that explain crucial clinical features of patients with EBV-associated diseases. Although we now have a better overview of the genetic diversity within EBV genomes, it has also become clear that defining phenotypic traits evinced by cells infected by different viruses usually result from the combination of multiple polymorphisms that will be difficult to identify in their entirety. However, the steadily increasing number of sequenced EBV genomes and cloned EBV BACS from diseased and healthy patients will facilitate the identification of the key polymorphisms that condition the biological and clinical behavior of the viruses. This will allow the development of preventative and therapeutic approaches against highly pathogenic viral strains. AU - Feederle, R. AU - Klinke, O.* AU - Kutikhin, A.* AU - Poirey, R.* AU - Tsai, M.H.* AU - Delecluse, H.J.* A2 - Münz, C.* C1 - 46966 C2 - 39112 CY - Berlin SP - 119-148 TI - Epstein–barr virus: From the detection of sequence polymorphisms to the recognition of viral types. JO - Curr. Top. Microbiol. Immunol. VL - 390 PB - Springer-verlag Berlin PY - 2015 SN - 0070-217x ER - TY - JOUR AB - Ever since the discovery of Epstein–Barr virus (EBV) more than 50 years ago, this virus has been studied for its capacity to readily establish a latent infection, which is the prominent hallmark of this member of the herpesvirus family. EBV has become an important model for many aspects of herpesviral latency, but the molecular steps and mechanisms that lead to and promote viral latency have only emerged recently. It now appears that the virus exploits diverse facets of epigenetic gene regulation in the cellular host to establish a latent infection. Most viral genes are transcriptionally repressed, and viral chromatin is densely compacted during EBV’s latent phase, but latent infection is not a dead end. In order to escape from this phase, epigenetic silencing must be reverted efficiently and quickly. It appears that EBV has perfected a clever strategy to overcome transcriptional repression of its many lytic genes to initiate virus de novo synthesis within a few hours after induction of its lytic cycle. This review tries to summarize the known molecular mechanisms, the current models, concepts, and ideas underlying this viral strategy. This review also attempts to identify and address gaps in our current understanding of EBV’s epigenetic mechanisms within the infected cellular host. AU - Hammerschmidt, W. C1 - 46964 C2 - 39143 CY - Berlin SP - 103-117 TI - The epigenetic life cycle of epstein–barr virus. JO - Curr. Top. Microbiol. Immunol. VL - 390 PB - Springer-verlag Berlin PY - 2015 SN - 0070-217x ER - TY - JOUR AB - While all herpesviruses can switch between lytic and latent life cycle, which are both driven by specific transcription programs, a unique feature of latent EBV infection is the expression of several distinct and well-defined viral latent transcription programs called latency I, II, and III. Growth transformation of B-cells by EBV in vitro is based on the concerted action of Epstein-Barr virus nuclear antigens (EBNAs) and latent membrane proteins(LMPs). EBV growth-transformed B-cells express a viral transcriptional program, termed latency III, which is characterized by the coexpression of EBNA2 and EBNA-LP with EBNA1, EBNA3A, -3B, and -3C as well as LMP1, LMP2A, and LMP2B. The focus of this review will be to discuss the current understanding of how two of these proteins, EBNA2 and EBNA-LP, contribute to EBV-mediated B-cell growth transformation. AU - Kempkes, B. AU - Ling, P.D.* A2 - Münz, C.* C1 - 46972 C2 - 39096 CY - Berlin SP - 35-39 TI - EBNA2 and its coactivator EBNA-LP. JO - Curr. Top. Microbiol. Immunol. VL - 391 PB - Springer-verlag Berlin PY - 2015 SN - 0070-217x ER - TY - JOUR AB - Almost exactly twenty years after the discovery of Epstein-Barr virus (EBV), the latent membrane protein 1 (LMP1) entered the EBV stage, and soon thereafter, it was recognized as the primary transforming gene product of the virus. LMP1 is expressed in most EBV-associated lymphoproliferative diseases and malignancies, and it critically contributes to pathogenesis and disease phenotypes. Thirty years of LMP1 research revealed its high potential as a deregulator of cellular signal transduction pathways leading to target cell proliferation and the simultaneous subversion of cell death programs. However, LMP1 has multiple roles beyond cell transformation and immortalization, ranging from cytokine and chemokine induction, immune modulation, the global alteration of gene and microRNA expression patterns to the regulation of tumor angiogenesis, cell-cell contact, cell migration, and invasive growth of tumor cells. By acting like a constitutively active receptor, LMP1 recruits cellular signaling molecules associated with tumor necrosis factor receptors such as tumor necrosis factor receptor-associated factor (TRAF) proteins and TRADD to mimic signals of the costimulatory CD40 receptor in the EBV-infected B lymphocyte. LMP1 activates NF-κB, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3-K), IRF7, and STAT pathways. Here, we review LMP1's molecular and biological functions, highlighting the interface between LMP1 and the cellular signal transduction network as an important factor of virus-host interaction and a potential therapeutic target. AU - Kieser, A. AU - Sterz, K. A2 - Münz, C.* C1 - 46971 C2 - 39095 CY - Berlin SP - 119-149 TI - The Latent Membrane Protein 1 (LMP1). JO - Curr. Top. Microbiol. Immunol. VL - 391 PB - Springer-verlag Berlin PY - 2015 SN - 0070-217x ER - TY - JOUR AB - Tumorigenesis has long been viewed as a problem of perturbed regulation of cell proliferation. It has, however, become increasingly apparent during the last years that disturbance of the equilibrium between cell survival and cell death may equally contribute to the development of a tumor. Elimination of cells has first been described by morphologists as an important physiological process in developmental biology for which the term programmed cell death (PCD) or apoptosis has been coined, and has since then been recognized as a generally important phenomenon in many different areas of biology (Wyllie et al., 1980). Apart from morphological criteria, apoptosis is only poorly defined and discrimination from other forms of cell death is often difficult. Regardless of the definition of apoptosis, it is apparent that susceptibility versus resistance to toxic conditions or death inducing signals is an extremely important property of a cell determining its fate in its environmental context.     AU - Bornkamm, G.W. AU - Richter, C. C1 - 40040 C2 - 37858 SP - 323-330 TI - A link between the antioxidant defense system and calcium: A proposal for the biochemical function of Bcl-2. JO - Curr. Top. Microbiol. Immunol. VL - 194 PY - 1994 SN - 0070-217x ER - TY - JOUR AU - Delecluse, H.J. AU - Kohls, S. AU - Bullerdiek, J. AU - Bornkamm, G.W. C1 - 20501 C2 - 13710 SP - 367-373 TI - Integration of EBV in Burkitt's Lymphoma Cells. JO - Curr. Top. Microbiol. Immunol. VL - 182 PY - 1992 SN - 0070-217x ER - TY - JOUR AU - Zimber-Strobl, U. AU - Suentzenich, K.-O. AU - Falk, M.H. AU - Laux, G. AU - Cordier, M. AU - Calender, A. AU - Billaud, M. AU - Lenoir, G.M. AU - Bornkamm, G.W. C1 - 18340 C2 - 11531 SP - 359-366 TI - Epstein-Barr Virus Terminal Protein Gene Transcription is Dependent on EBNA2 Expression and Provides Evidence for Viral Integration into the Host Genome. JO - Curr. Top. Microbiol. Immunol. VL - 166 PY - 1990 SN - 0070-217x ER - TY - JOUR AU - Zimber-Strobl, U. AU - Suentzenich, K.O. AU - Falk, M. AU - Laux, G. AU - Cordier, M.P. AU - Calender, A. AU - Billaud, M. AU - Lenoir, G.M. AU - Bornkamm, G.W. C1 - 41910 C2 - 0 SP - 359-366 TI - Epstein-Barr virus terminal protein gene transcription is dependent on EBNA2 expression and provides evidence for viral integration into the host genome. JO - Curr. Top. Microbiol. Immunol. VL - 166 PY - 1990 SN - 0070-217x ER -