Abstract
In the years following the first report of the finding of what became known as Epstein-Barr virus (EBV) (Epstein et al., 1964), various limited aspects of the discovery were described in book chapters and published lectures (Epstein, 1970; Epstein and Achong, 1979a; Epstein, 1984, 1985) with rather moderate circulations. Nevertheless, the outlines of the story could be pieced together by those interested in knowing the events which led to a whole new area in virology with important implications for viral carcinogenesis, immunology, and later even the treatment and prevention of certain human malignancies. This initial chapter is hoped to provide a concise account of the discovery and initial characterization of EBV.
Abstract
Werner and Gertrude Henle were early pioneers in Epstein-Barr virus (EBV) research. Their seroepidemiological studies resulted in the discovery of EBV as causative agent of infectious mononucleosis. Between the years 1966 and 1987 they characterized the seroresponse to viral capsid and early antigens, demonstrated the ubiquity and global distribution of EBV infections, and identified specific antibody patterns in patients with EBV-linked tumors. In addition, they were the first to demonstrate the transforming properties of EBV. Their ground-breaking work formed the basis for the large number of subsequent studies on the role of EBV in human pathogenesis and human tumors.
Abstract
The initial studies of Epstein-Barr virus (EBV) were a difficult foray into the study of human cancer and the contributions of viruses to the development of these cancers. Accepting the fact that viruses were a major cofactor in contributing to the development of cancers had little support from some factions. However, the discovery of herpesvirus particles in cells isolated from a human Burkitt's lymphoma was nonetheless thrilling. This chapter is meant to bring the major concepts of tumor virology as an integral part and what we understand about the functions of the regulation of the cellular p53 and pRb tumor suppressor pathways by EBV in contrast to that of the small DNA tumor viruses.
Abstract
EBV is an ubiquitous virus, which under different environmental conditions, initiates or promotes various malignant proliferations. Sero epidemiology has played a key role in providing evidence for an etiological role of EBV in the development of three preeminent diseases, namely teenagers' infections mononucleosis in western countries, B cell lymphomas as described by Burkitt (BL) in sub-Sahara African children, and nasopharyngeal carcinoma (NPC) in South East Asia among Cantonese Chinese.
Abstract
Epstein-Barr virus (EBV) is the cause of heterophile-positive infectious mononucleosis. Symptoms are predominantly due to proliferation of T cells reacting to virus-infected B cells. Most cases are self limited and do not require therapy. Patients with chronic active EBV have persistent disease due to inability to control the virus and often die of B or T cell lymphoproliferative disease. Patients with the X-linked lymphoproliferative syndrome infected with EBV usually succumb to fulminant infectious mononucleosis. Organ or stem cell transplant recipients may develop EBV lymphoproliferative disease and reduction of immunosuppression, interferon-alpha, anti-CD20 antibody, or infusions of EBV-specific T cells have been effective in many patients. A number of malignancies have been associated with EBV including Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin's disease, nonHodgkin's lymphoma in patients with AIDS, T/NK cell lymphoma, gastric carcinoma, smooth muscle tumors, and lymphomatoid granulomatosis. Many of these tumors show different patterns of latent EBV gene expression.
Abstract
Epstein-Barr virus (EBV) is transmitted through saliva and is periodically shed throughout the life of virus carriers in oral secretions. The well-known association of EBV with lymphoid and epithelial cell malignancies has prompted numerous investigations into whether malignancies of the oral cavity, occurring in proximity of sites of natural EBV replication, preferentially harbor EBV. Attempts to define pathologic relationships in the context of an anatomic site with intrinsic viral activity highlight difficulties inherent in establishing valid clinical correlations between this ubiquitous herpesvirus and disease. Recent literature on EBV in oral cavity malignancies underscores, on the one hand, the technical challenges that confound the conclusive delineation of such links and, on the other, has suggested alternative roles for EBV in human malignancy as a guide to future clinical investigation.
Abstract
Nasopharyngeal carcinoma (NPC) is an epithelial tumor that is characterized by marked geographic and population differences in incidence and is consistently associated with the Epstein-Barr virus. The EBV genome is clonal within the tumor suggesting that the tumor is a clonal proliferation of an EBV infected cell. Within the tumor, the viral infection is latent with expression of the EBV proteins EBNA1, LMP1, LMP2 and the EBER and BamHI A RNAs. LMP1 and LMP2 have profound effects on cell growth regulation. LMP1 activates NFκB and a specific form of NFκB is detected in NPC tumors. LMP2 activates the Akt kinase which inactivates the GSK3β kinase and induces β-catenin regulated expression in epithelial cells. In NPC tumors activated GSK3β and nuclear β-catenin are detected. the malignant cells continue to express multiple viral proteins. The continued expression of these viral proteins provides multiple opportunities to target the viral proteins and their properties using immuno-therapy, inhibitors of critical activated pathways, or specific molecular therapy directed toward the viral functions.
Abstract
Although the morphology of the pathognomonic Reed-Sternberg cells of Hodgkin's lymphoma (HL) was described over a century ago, it was not until recently that the origin of these cells from germinal centre B cells was recognised. The demonstration that a proportion of HL tumours harbours the Epstein-Barr virus (EBV) and that its genome is monoclonal in these tumours suggests that the virus contributes to the development of HL in some cases. This review summarises current knowledge of the pathogenesis of HL with particular emphasis on the association with EBV.
Abstract
Endemic Burkitt's lymphoma (BL) is sometimes called 'African Burkitt's lymphoma' because it occurs at the highest frequencies in children in Equatorial Africa. It also is a major childhood cancer, albeit occurring in lower frequencies, in locations as diverse as Papua, New Guinea and Bahia, northeastern Brazil. This intriguing geographical bias is only partly explainable. Endemic BL, as with sporadic and immunodeficiency-related BL, shares translocations that involve the oncogenic c-myc and immunoglobulin genes, but how, and to what extent, these tumors differ in their properties is still a matter for debate and exploration. Wright (1999) asked the question, 'what is Burkitt's Lymphoma and when is it endemic'? We address in more detail this query but, like him, cannot provide a wholly satisfactory answer. For the moment, the numbers of children who still succumb to BL is great enough that other topics, from an humanitarian point of view, may rightly be deemed to take precedence in dealing with this malignancy. However, the control and/or containment of this tumor, in the longer term, may rely on solving some of the problems that deal with endemic aspects of the disease.
Abstract
Epstein-Barr virus (EBV), which is known to be associated with nasopharyngeal carcinoma, has recently become linked with a growing list of carcinomas. The presence of the EBV genome in a subset of breast cancers has been detected but the results remain disparate. When detected, the overall viral load was found to be low and heterogeneous within the same tumor as well as amongst different tumors. The type of cells the virus has infected remains a matter of debate although different data favor the inference that EBV is harbored by epithelial cells: i) The EBV genome was detected in tumor cells isolated by laser capture microdissection ii) the pattern of EBV gene expression observed in breast tumors is different to what was described in peripheral blood lymphocytes suggesting that EBV expression was due to virus from epithelial cells and not from infiltrating lymphocytes. The possible role of EBV in breast cancer development or progression is discussed.
Abstract
Recent studies have revealed the association of the Epstein-Barr virus (EBV) with about 10% of gastric cancer cases worldwide. EBV is found in 100% of cancer cells of the EBV-associated gastric cancer cases. In addition, EBV DNA in cancer biopsies shows monoclonality, indicating that carcinoma arises from a single EBV-infected cell. These findings suggest that EBV plays an important role in the development of EBV-positive gastric cancers. The difficulty of establishment of EBV infection of epithelial cells in vitro has hampered the study of the role of EBV in epithelial malignancies. The development of an in vitro model of EBV-infection with recombinant EBV carrying a selectable marker has enabled this difficulty to be overcome and has made it possible to establish EBV-infected primary cultured gastric epithelial cells. The cells express EBV genes identical to those typically observed in EBV-positive gastric cancer, and show accelerated malignant properties, suggesting that EBV contributes to the maintenance of the malignant phenotype of EBV-positive gastric cancer. Recently, functional studies of EBV genes in epithelial cells have been carried out to clarify the mechanisms of EBV-associated gastric cancer development.
Abstract
In addition to its central role in transformation of cells by EBV, the LMP-1 protein is able also to induce directly a comprehensive set of factors that promote tumor progression. These are cellular factors that mediate steps in the process of invasion and metastasis of tumor cells as well as angiogenesis. Principal functions and factors identified to date, most induced by LMP-1, include cell detachment (MUC1); penetration of basement membrane (MMP-9 and MMP-1); and increase in cell motility (α v integrins). Other viral genes may contribute to cell mobility (LMP2A) and counteraction of the metastatic suppressor protein, Nm23-H1 (EBNA-3C). Neoangiogenesis is also essential for invasion by tumor cells both locally and at distant sites. LMP-1 induces key factors that mediate this complex process including IL-8, FGF2, COX2, HIF1α and VEGF. Both NPC (Type II latency) and B-lymphoproliferative diseases (Type III latency) are highly invasive, and expression of LMP-1 in vivo correlates with invasive indices for NPC. Thus EBV may as an alternative or addition to an etiologic relation to its associated tumors exert the capacity to alter later stages of malignant progression of existing tumor cells.
Abstract
Epstein-Barr virus (EBV) is a ubiquitous human tumor virus that has probably shaped the human immune system in its long co-evolution with man. Its persistent infection is immune controlled by strong cell-mediated adaptive immunity mainly via T cells. Initiation of this immune control involves cells of the innate immune system. Dendritic cells likely activate Natural Killer cells at the beginning of an EBV specific immune response and these then limit viral burden as well as assist in the polarization of the DC primed T cell response. The result is anti-viral Th1 immunity that keeps most EBV carriers free of EBV associated malignancies for their lifetime. This chapter will highlight the composition of EBV specific immune control and point out features of the human immune system that might have evolved for better immunity against EBV as well as strategies utilized by the virus to evade the host immune response.
Abstract
Superantigens are microbial proteins that strongly stimulate T cells. A human endogenous retroviral superantigen is expressed after Epstein-Barr virus (EBV) infection. The superantigen gene is located on chromosome 1, and is encoded by the envelope (env) gene of human endogenous retrovirus HERV-K18. The EBV latent membrane proteins are sufficient for transactivation of HERV-K18 env. In this chapter, we review the literature on viral superantigens, and summarize the evidence leading to the discovery of the EBV associated superantigen. In light of these findings, we discuss a possible role for the superantigen associated T cell activation in EBV biology, and postulate how this strong immune activation might at times enhance the ability of EBV ability to cause disease.
Abstract
A genetic map has been compiled for Epstein-Barr virus using published features annotated to the EBVwt sequence. EBVwt was assembled from the B95-8 and Raji sequences, which were determined experimentally. The detailed annotation for the summary map illustrated in this chapter is available from the EMBL or Genbank databases under accession number AJ507799.
Abstract
Epstein-Barr virus (EBV) infects B-lymphocytes and then persists as an incomplete or "latent" virus in order to evade immune recognition while it expresses twelve gene products that efficiently transform cell growth into long-term proliferating lymphoblastoid cell lines. In healthy individuals, EBV's oncogenic strategy for persistence is restricted by adaptive immune responses, but the viral infection is not completely cleared. Thus, most adults are life-long asymptomatic carriers who routinely shed virus in saliva. In immuno-compromised individuals, EBV infected B-lymphocytes may progress to a malignant lymphoproliferative disease. EBV's strong association with the development of this and other malignancies has sparked considerable interest in understanding the molecular basis of transformation mediated by latent EBV gene expression. This article reviews the techniques that have been developed to expand our understanding of the molecular pathogenesis of EBV-mediated transformation.
Abstract
This chapter will cover the current state of knowledge about how Epstein-Barr virus establishes and maintains persistent infection in vivo. EBV is a B lymphotrophic virus whose biology is closely entwined with the normal biology of B lymphocytes. Recent studies have led to a model of EBV persistence based on the idea that the virus uses all aspects of mature B cell biology to establish (activation and germinal center differentiation) and maintain (memory) persistent infection and to replicate (plasma cells). To achieve this, the virus uses different transcription programs in different cellular backgrounds. The virus activates and drives the growth of newly infected B cells, using the growth program, so that the cell can then differentiate, using the default program, via the germinal center reaction into the memory compartment. EBV persists within the long lived memory B cell compartment (latency and EBNA1 only programs) where it shuts down all viral protein expression, so it is neither pathogenic to the host nor detectable by the immune response. If the infected memory cell differentiates into a plasma cell the virus is released for further infectious spread. This model provides an explanation for the disparate behavior of EBV in different cell types and suggests that the EBV associated lymphomas arise from specific stages in the life cycle of EBV.
Abstract
Epstein-Barr virus (EBV) is a highly, but not exclusively lymphotropic virus. It has variously been reported to infect macrophages, smooth muscle cells, T cells, and natural killer cells. However, the second major target of the virus is generally accepted to be the epithelial cell. Epithelial cell malignancies comprise a large part of the burden of EBV-associated disease worldwide and epithelial cells may play an important role in the spread of virus both between and within hosts. Our understanding of how virus initiates infection of either a B cell or an epithelial cell is incomplete, but several of the key virus and cell proteins involved in B cell infection have been identified. Less is clear about the important players in epithelial cell infection, where a very different picture is gradually emerging. This chapter summarizes what we currently know about early events in epithelial infection and contrasts it with the models that have been derived from the more extensive and comprehensive work done on B cells. It also explores how replication of virus in each cell type may influence virus trafficking, transmission and persistence.
Abstract
Epstein-Barr virus (EBV) is a particularly successful human parasite; it successfully establishes life-long latent infections in a large majority of all people. EBV is also a strikingly successful cellular parasite that in some cases contributes to its host cell's survival. In this chapter we describe how EBV's plasmid replicon underlies all viral contributions to the latent infection of cells. These contributions provide the infected cells advantages that ensure the maintenance of EBV even in a proliferating population of cells and thus also can underlie EBV's contributions to human cancers.
Abstract
The association of Epstein-Barr virus (EBV) with a number of cancers, and the ability of EBV to latently infect and immortalize B cells in vitro, has led to an intense interest in identifying the mechanisms by which EBV is able to transform B cells. To identify viral genes involved in B cell growth transformation, an extensive effort was mounted to identify transcriptionally active regions of the viral genome in various lymphoblastoid cell lines (LCLs) and Burkitt lymphoma (BL) cell lines. These studies ultimately revealed that transcription of the genes encoding the EBV latency-associated antigens is singularly complex and intriguing. This chapter will focus on what we have learned about transcription of the Epstein-Barr nuclear antigen (EBNA) genes and the latency-associated membrane protein (LMP) genes, as well as speculate about mechanisms that may be involved in regulating EBV gene expression.
Abstract
Epstein-Barr virus (EBV)-encoded small nonpolyadenylated RNAs (EBERs) are the most abundant viral transcripts in latently EBV-infected cells. However, their roles in viral infection were long totally unknown. Recently, several reports demonstrated that EBERs play a key role in oncogenesis. EBERs confer resistance to interferon _-induced apoptosis by directly binding to double-stranded RNA-activated protein kinase and inhibiting its phosphorylation. Alternatively, EBERs can also induce the expression of cellular growth factors. EBERs induce the expression of interleukin-10 in B cells, interleukin-9 in T cells, and insulin-like growth factor-1 in epithelial cells, each of which acts as an autocrine growth factor. These studies open the way towards supporting a new concept that RNA molecules can contribute to the oncogenic process.
Abstract
In vitro and upon primary infection in vivo, Epstein-Barr virus (EBV) infects resting B-cells and transforms them into proliferating lymphoblasts with a remarkable efficiency. Nine virally encoded proteins and a limited number of cellular proteins are expressed under the control of a master transcription factor, the EBV nuclear antigen 2 (EBNA2), and play a decisive role in the transformation process. While much is known at the molecular level about the EBNA2-dependent expression program of EBV genes, the pattern of cellular target genes remains poorly defined. However, it is known that EBNA2 specifically up-regulates expression of the B-cell activation marker CD23, the complement and EBV receptor CD21, the chemokine receptor BLR2/EBI1 and the AP-1 family member BATF, and activates the proto-oncogenes c-fgr and c-myc, the latter of which seems to be the most prominent cellular target essential for the ability of EBNA2 to transform B-cells. Here, we review current knowledge of the molecular mechanisms by which EBNA2 controls viral and cellular gene expression in order to promote lymphoproliferation.
Abstract
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 spectrum of activated target genes. The recent finding that cellular effector proteins of EBNA-2 are also part of the signalling pathways activated by the Notch transmembrane receptor has suggested that EBNA-2 might be the viral functional analogue of the Notch signalling cascade. This review describes the common denominators of EBNA-2 and Notch signalling pathways and will try to integrate our current knowledge on the physiological role of Notch activation in lymphocyte development and differentiation as well as on the role of activated Notch in lymphocyte malignancies.
Abstract
Epstein-Barr virus (EBV) is the causative agent of post-transplant lymphoproliferative disease (PTLD) and is strongly associated with other human malignancies including endemic Burkitt's lymphoma, nasopharyngeal carcinoma, and some subtypes of Hodgkin's disease. Through the expression of nine latency proteins, a subset of which are absolutely essential, EBV activates and drives the proliferation of B-lymphocytes in vitro resulting in indefinitely proliferating lymphoblastoid cell lines (LCLs). The small DNA tumor viruses have classically been linked to cell cycle deregulation, presumably a necessary step in cell immortalization/transformation. Specifically, adenovirus, the polyomavirus SV40, and human papillomavirus express specific viral antigens that bind and modulate the function of critical cell cycle gatekeepers such as the retinoblastoma protein and p53. By comparison, the links between EBV latency antigens and cell cycle regulators have remained tenuous. Here, we will examine current evidence implicating EBV latency antigens in cell cycle deregulation. This review focuses on four latency proteins EBNA2, EBNA-LP, EBNA3C, and LMP1. EBNA2 in cooperation with EBNA-LP facilitates cell cycle entry and regulates the cyclin D2 promoter. EBNA3C also facilitates passage through the G1/S restriction point, and additionally targets S-phase cyclins. LMP1 clearly provides anti-apoptotic signals to the cell and potentially also targets the cyclin D2 promoter. We will attempt to assimilate these and other single gene studies into a model that explains how EBV utilizes its latency proteins to fulfil unique requirements in the stimulation of B cell proliferation and how this may distance EBV from other DNA tumor viruses.
Abstract
Latent membrane protein 2A (LMP2A) is expressed both in normal EBV latency and EBV-associated pathogenesis. This persistent expression indicates that LMP2A likely functions in key aspects of EBV latency and in disease manifestations in the human host. Functional studies of LMP2A has has revealed that LMP2A mimics BCR-mediated signal transduction and activates anti-apoptotic and cell-survival signals. To regulate its own function, LMP2A utilizes ubiquitin-dependent processes which may allow LMP2A to modulate B cell differentiation and establish latent infection in memory B cells. Recent studies have showed that, despite the dispensability of LMP2A in EBV-induced B cell transformation, LMP2A has potent transforming activities in epithelial cells. Moreover, DNA microarray analysis suggests an important role of LMP2A in the development and pathogenesis of Hodgkin's Lymphoma. In summary, it appears that LMP2A plays a key role in the establishment of EBV latent infection and the development of EBV-related pathogenesis such as nasopharyngeal carcinoma and Hodgkin's Lymphoma. This chapter will focus on what is known of LMP2A function in B cells and epithelial cells.
Abstract
Epstein-Barr Virus (EBV) Latent Infection Membrane Protein 1 (LMP1) is expressed in latency III primary EBV infection of human B lymphoblasts, in vivo, in latency III post-transplant lymphoproliferative disease, in EBV latency III infected human B lymphocytes that have been converted into lymphoblasts capable of long term proliferation, in vitro (LCLs), in EBV associated Hodgkin's Disease, and in many nasopharyngeal cancers. LMP1 expression in human B lymphoma cells induces activation and adhesion molecule expression and cell clumping, which are characteristic of LCLs or of CD40 activated B lymphocytes. In immortalized fibroblasts, LMP1 mimics aspects of activated ras in enabling serum, contact, and anchorage independent growth. Reverse genetic analyses implicate the LMP1 6 transmembrane and 2 C-terminal cytoplasmic domains as the essential domains for LMP1 effects. The 6 transmembrane domains cause intermolecular interaction, whereas the C-terminal domains signal through tumor necrosis factor receptor (TNFR) associated factors or death domain proteins and activate NF-κB, JNK, and p38. Comparisons of LMP1 and TNFR signal transduction provides insights into the biology and chemistry of these pathways. Biochemical interactions among LMP1 transmembrane domains and lipid rafts are critical for signaling and NF-κB activation is essential for cell survival. Studies of the chemistry and biology of LMP1 effects are important for controlling EBV infected cell survival and growth.
Abstract
Reactivation of lytic EBV infection from latently infected cells is a highly regulated process that begins when expression of immediate-early (IE) viral genes is triggered by host cell transcription factors. The IE gene products are transcriptional transactivators that initiate a cascade of lytic viral gene expression. The early viral genes encode viral proteins that initiate replication of the viral genome from the oriLyt site. Late viral gene transcription occurs following viral replication, allowing expression of structural proteins. The viral genome is then packaged within a capsid to generate transmissible virions.
Abstract
Of the approximately 90 genes encoded by the EBV genome, two viral oncogenes, LMP1 and BARF1, were known to induce a malignant transformation when introduced into rodent fibroblasts. LMP1 and BARF1 are expressed in 50% and 90% respectively, of cases of invasive NPC. BARF1 transcripts are detected in almost 100% of EBV-positive gastric carcinomas and in epithelial cells immortalized by NPC-derived EBV, however these cells are consistently negative for LMP1. The BARF1 oncogene is capable of immortalizing a monkey kidney epithelial cell line in vitro and of inducing malignant transformation in several established cell lines including rodent fibroblast and human B cell lines. In these cells, the expression of cellular proteins like telomerase, Bcl2, c-myc, CD21, CD23 and CD71 was activated. N-terminal sequence (1 to 54 aa) of the BARF1 protein was sufficient to induce malignant transformation and to activate Bcl2 expression. Purified BARF1 protein was capable of activating the cell cycle of rodent fibroblasts, primary monkey epithelial cells and the human B cell line by an autocrine/paracrine mechanism suggesting that this protein can behave as a growth factor. On the other hand, BARF1 is involved in immunomodulation: secreted BARF1 protein formed a complex with purified CSF1 molecule, so that the activation of macrophage in vitro was inhibited. BARF1 negative virus was capable of signicantly inhibiting secretion of interferon. BARF1 protein expressed in a human B cell line by transfection was recognized by Natural Killer cells (NK) in ADCC (Antibody Dependent Cell Cytotoxity) test. These observations suggest that BARF1 can intervene not only in immunomodulation, but also in the oncogenic process.
Abstract
The EBV SM protein is a member of a highly conserved family of proteins present in most herpesviruses known to infect mammals. There is a significant amount of functional and sequence divergence among the different homologs encoded by the human herpesviruses, including the stage of lytic replication during which they are expressed, differences in mechanism of action, and varying effects on splicing and transcription. SM is an early antigen having multiple post-transcriptional gene-regulatory functions shown to be essential for lytic EBV replication. SM enhances expression of EBV lytic genes and has both positive and negative effects on cellular gene expression. In addition to enhancing accumulation of EBV gene mRNAs, SM also has important effects on cellular mRNAs, significantly altering the host cell transcriptional profile.
Abstract
The past ten years have seen a dramatic accumulation of insights into the biology, immunology and virology of EBV so that for the first time rational vaccine development can begin. Thus the targets molecules present on latency I, II and III diseases have been well defined and the relative importance of both the cellular and the humoral responses are understood at least in the broad sense. Several vaccine trials towards infectious mononucleosis (IM) and post-transplant lymphoproliferative disease (PTLD) have been conducted and others are planned. While formulating vaccines for nasopharyngeal carcinoma (NPC) and Hodgkin's lymphoma (HL) are more speculative, there is good reason to believe that formulations encompassing cytotoxic T cell (CTL) epitopes encoded by LMP1 and LMP2 should have therapeutic benefit. On the other hand, there is little prospect for a vaccine to reverse the rapid growth of Burkitt's lymphoma.
Abstract
The idea of using the immune system to control cancer in human derives from the concept of "immune surveillance" proposed by Burnet in early 1950. The adoptive transfer of antigen specific cytotoxic T-cells represent one the most advanced efforts to translate this concept in a clinical application. New tumor-associated antigens are continuously being identified and proposed as potential targets for immunotherapy of human malignancies. Other tumors are clearly associated with viral infections, and Epstein Barr Virus (EBV) related tumors express immunogenic viral proteins that make them particularly attractive for immunotherapy approaches. Over the last ten years major efforts to optimize clinical grade protocols for ex vivo expansion of EBV-specific cytotoxic T-lymphocytes (CTL) have been made. In this chapter we will summarize the clinical experiences of CTL adoptive transfer in different EBV-related diseases including Post Transplant Lymphoproliferative Disorders (PTLD), Hodgkin's lymphoma (HD), Nasopharyngeal carcinoma (NPC) and Severe Chronic EBV infection (SCAEBV). We also will discuss the limitations and the future strategies to improve the efficiency of this approach as well as potential applications in non-EBV related tumors.
Abstract
There is a renewed interest in the EBV-related herpesviruses belonging to the lymphocryptovirus (LCV) genus that naturally infect nonhuman primates. It has been long recognized that virtually all species of Old World nonhuman primates are naturally infected with their own LCV, but interest has been restimulated by the ability to experimentally infect naive rhesus macaques with rhesus LCV and the development of an animal model that accurately reproduces many aspects of EBV infection in humans. The recent derivation of the complete rhesus LCV genome sequence shows identity of the viral gene repertoire between EBV and rhesus LCV and provides genetic validation for rhesus LCV infection as an experimental system to model and study EBV pathogenesis. The recent discovery of LCV infecting New World primates indicates that EBV-related herpesviruses evolved earlier than previously believed, and the full length marmoset LCV genome sequence provides unique insight into the evolution of this tumor-associated herpesvirus genus. These recent advances have provided a much better understanding of EBV's closest relatives, as well as new laboratory and animal model systems for studying the molecular biology and pathogenesis of EBV infection.
Abstract
By drawing together some of the key findings and issues of debate described in the earlier chapters, this summary aims to show how our current understanding of EBV biology and disease pathogenesis was gained, to identify the strengths and weaknesses of our current position, and to consider what are the most important challenges for the future.
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