Discovery Of Epstein-Barr Virus Research Articles

Recent Advances in Assessing the Clinical Implications of Epstein-Barr Virus Infection and Their Application to the Diagnosis and Treatment of Nasopharyngeal Carcinoma.

Reports about the oncogenic mechanisms underlying nasopharyngeal carcinoma (NPC) have been accumulating since the discovery of Epstein-Barr virus (EBV) in NPC cells. EBV is the primary causative agent of NPC. EBV-host and tumor-immune system interactions underlie the unique representative pathology of NPC, which is an undifferentiated cancer cell with extensive lymphocyte infiltration. Recent advances in the understanding of immune evasion and checkpoints have changed the treatment of NPC in clinical settings. The main EBV genes involved in NPC are LMP1, which is the primary EBV oncogene, and BZLF1, which induces the lytic phase of EBV. These two multifunctional genes affect host cell behavior, including the tumor-immune microenvironment and EBV behavior. Latent infections, elevated concentrations of the anti-EBV antibody and plasma EBV DNA have been used as biomarkers of EBV-associated NPC. The massive infiltration of lymphocytes in the stroma suggests the immunogenic characteristics of NPC as a virus-infected tumor and, at the same time, also indicates the presence of a sophisticated immunosuppressive system within NPC tumors. In fact, immune checkpoint inhibitors have shown promise in improving the prognosis of NPC patients with recurrent and metastatic disease. However, patients with advanced NPC still require invasive treatments. Therefore, there is a pressing need to develop an effective screening system for early-stage detection of NPC in patients. Various modalities, such as nasopharyngeal cytology, cell-free DNA methylation, and deep learning-assisted nasopharyngeal endoscopy for screening and diagnosis, have been introduced. Each modality has its advantages and disadvantages. A reciprocal combination of these modalities will improve screening and early diagnosis of NPC.

Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires.

ABSTRACTFifty years after the discovery of Epstein-Barr virus (EBV), it remains unclear how primary infection with this virus leads to massive CD8 T-cell expansion and acute infectious mononucleosis (AIM) in young adults. AIM can vary greatly in severity, from a mild transient influenza-like illness to a prolonged severe syndrome. We questioned whether expansion of a unique HLA-A2.01-restricted, cross-reactive CD8 T-cell response between influenza virus A-M158 (IAV-M1) and EBV BMLF1280 (EBV-BM) could modulate the immune response to EBV and play a role in determining the severity of AIM in 32 college students. Only ex vivo total IAV-M1 and IAV-M1+EBV-BM cross-reactive tetramer+ frequencies directly correlated with AIM severity and were predictive of severe disease. Expansion of specific cross-reactive memory IAV-M1 T-cell receptor (TCR) Vβ repertoires correlated with levels of disease severity. There were unique profiles of qualitatively different functional responses in the cross-reactive and EBV-specific CD8 T-cell responses in each of the three groups studied, severe-AIM patients, mild-AIM patients, and seropositive persistently EBV-infected healthy donors, that may result from differences in TCR repertoire use. IAV-M1 tetramer+ cells were functionally cross-reactive in short-term cultures, were associated with the highest disease severity in AIM, and displayed enhanced production of gamma interferon, a cytokine that greatly amplifies immune responses, thus frequently contributing to induction of immunopathology. Altogether, these data link heterologous immunity via CD8 T-cell cross-reactivity to CD8 T-cell repertoire selection, function, and resultant disease severity in a common and important human infection. In particular, it highlights for the first time a direct link between the TCR repertoire with pathogenesis and the diversity of outcomes upon pathogen encounter.

Abstract IA38: Viral cancers: The forgotten culprits in the African cancer problem

Abstract Infection is responsible for approximately one-fifth of cancer cases worldwide. Causes and rates of cancer vary dramatically throughout the world. While infection is often overlooked as a cancer cause in the United States and Europe, it is often the main driving force for cancer in other parts of the world. The first human cancer virus discovered, Epstein-Barr virus (EBV), was isolated from a Ugandan Burkitt lymphoma in 1964. Infectious cancers including hepatocellular carcinoma, cervical carcinoma, Kaposi's sarcoma and gastric carcinoma represent the majority of cancer cases among men and women in some world regions, particularly in Africa. This lecture will focus on how new cancer viruses can be discovered, using Kaposi sarcoma herpesvirus and Merkel cell polyomavirus found in our lab as examples. The common characteristics--as well as the diverse nature--of viral cancers will be described. The extraordinary public health success of vaccines in preventing cancers of particular importance in Africa will be highlighted, and missed opportunities for low-cost, effective prevention and treatment of infectious cancers will be discussed. As with discovery of EBV, it is quite possible that the next cancer agent will be discovered in cancers unique to African countries but will have important implications to public health throughout the world. Citation Format: Patrick S. Moore. Viral cancers: The forgotten culprits in the African cancer problem [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA38.

Viral Causes of Lymphoma: The History of Epstein-Barr Virus and Human T-Lymphotropic Virus 1.

In 1964, Epstein, Barr, and Achong published a report outlining their discovery of viral particles in lymphoblasts isolated from a patient with Burkitt lymphoma. The Epstein-Barr virus (EBV) was the first human cancer virus to be described, and its discovery paved the way for further investigations into the oncogenic potential of viruses. In the decades following the discovery of EBV, multinational research efforts led to the discovery of further viral causes of various human cancers. Lymphomas are perhaps the cancer type that is most closely associated with oncogenic viruses: infection with EBV, human T-lymphotropic virus 1 (HTLV-1), human immunodeficiency virus (HIV), Kaposi sarcoma-associated herpesvirus/human herpesvirus 8, and hepatitis C virus have all been associated with lymphomagenesis. Lymphomas have also played an important role in the history of oncoviruses, as both the first human oncovirus (EBV) and the first human retrovirus (HTLV-1) were discovered through isolates taken from patients with unique lymphoma syndromes. The history of the discovery of these 2 key oncoviruses is presented here, and their impact on further medical research, using the specific example of HIV research, is briefly discussed.

Epstein-Barr virus infection of infants: implications of early age of infection on viral control and risk for Burkitt lymphoma

Since its first description by Denis Burkitt, endemic Burkitt's lymphoma (BL), the most common childhood cancer in sub-Saharan Africa, has led scientists to search for clues to the origins of this malignancy. The discovery of Epstein-Barr virus (EBV) in BL cells over 50 years ago led to extensive sero-epidemiology studies and revealed that rather than being a virus restricted to areas where BL is endemic, EBV is ubiquitous in the world's population with an estimated greater than 90% of adults worldwide infected. A second pathogen, Plasmodium falciparum (P. falciparum) malaria is also linked to BL. In this review, we will discuss recent studies that indicate a role for P. falciparum malaria in dysregulating EBV infection, and increasing the risk for BL in children living where P. falciparum malaria transmission is high.

The Latent Membrane Protein 1 (LMP1).

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.

The Epigenetic Life Cycle of Epstein-Barr Virus.

Ever since the discovery of Epstein-Barr virus (EBV) more than 50years 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.

Host genetics of Epstein-Barr virus infection, latency and disease.

Epstein–Barr virus (EBV) infects 95% of the adult population and is the cause of infectious mononucleosis. It is also associated with 1% of cancers worldwide, such as nasopharyngeal carcinoma, Hodgkin's lymphoma and Burkitt's lymphoma. Human and cancer genetic studies are now major forces determining gene variants associated with many cancers, including nasopharyngeal carcinoma and Hodgkin's lymphoma. Host genetics is also important in infectious disease; however, there have been no large-scale efforts towards understanding the contribution that human genetic variation plays in primary EBV infection and latency. This review covers 25 years of studies into host genetic susceptibility to EBV infection and disease, from candidate gene studies, to the first genome-wide association study of EBV antibody response, and an EBV-status stratified genome-wide association study of Hodgkin's lymphoma. Although many genes are implicated in EBV-related disease, studies are often small, not replicated or followed up in a different disease. Larger, appropriately powered genomic studies to understand the host response to EBV will be needed to move our understanding of the biology of EBV infection beyond the handful of genes currently identified. Fifty years since the discovery of EBV and its identification as a human oncogenic virus, a glimpse of the future is shown by the first whole-genome and whole-exome studies, revealing new human genes at the heart of the host–EBV interaction. © 2014 The Authors. Reviews in Medical Virology published by John Wiley & Sons Ltd.

Epstein-Barr Virus Turns 50

Fifty years after the discovery of Epstein-Barr virus and its association with cancer, a vaccine or therapy for the virus remains elusive.

Epstein–Barr Virus, the Immune System, and Associated Diseases

Host immune system is designed (or evolved) to fight against different pathogens. Many viruses infect the immune cells for the propagation of new progenies, thus the infection may modulate the host immune homeostasis. It has been more than 45 years since the discovery of Epstein–Barr virus (EBV) from a Burkitt's lymphoma derived cell line. The ability of EBV to transform primary B cells in vitro leads to the suggestion for its oncogenic potential. However, except the clear understanding of the role of EBV in post-transplantation lymphoproliferative disease, it remains ambiguous why such a ubiquitous virus causes malignant diseases only in a very small subset of individuals. Possible explanation is that EBV may cooperate with other environmental and host genetic factors and lead to the development of EBV associated neoplastic diseases. In addition to infecting B cells, recent studies revealed that EBV may impact host immune system more broadly than previously thought, for example the development of regulatory NKT subsets. Instead of an intensive review, this article aims to provide a linkage to recent advances on the interplay between EBV and host immune system and to inspire further studies on EBV related diseases, especially autoimmune diseases.

Presence and role of Simian Virus 40 (SV40) in malignant pleural mesothelioma

Background. Evidence of a possible role of viruses in cancer first emerged in the early 1900s and was confirmed after the discovery of Epstein-Barr virus (EBV) in Burkitt’s lymphoma cells. Thereafter, several oncogenic viruses and retroviruses were characterised. It is estimated that 15% of human malignancies are of viral aetiology. Oncogenic viruses use different proteins to interfere dramatically with the cellular cell cycle and affect many signalling pathways and checkpoints, causing genomic instability, immunoresistance and immortality. Conclusions. Simian virus 40 (SV40) is a small DNA virus from the genus polyomavirus, closely related to human polyomaviruses John Cunningham virus (JCV) and BK virus (BKV) and is highly oncogenic for rodents. The virus accidentally entered the human population through contaminated early batches of polio vaccine in the 1960s. After the discovery of SV40-like DNA sequences in mesothelioma samples in 1994, a new wave of research started, focusing on the role of SV40 in malignant pleural mesothelioma and human cancer in general. Although the virus is not considered a cancer causing agent for humans, it is thought to have a (not yet defined) role in the development of the malignancy. Further research to better understand the interactions between the virus and the mesothelial cell is still ongoing.

Burkitt lymphoma in Uganda: 50 years of ongoing discovery

W hile working in Uganda, a physician by the name of Denison Parson Burkitt first described the tumor that now carries his name. In 1957, Dr. Burkitt, along with his colleagues, examined a child with what appeared to be swelling along the jaw. After observing a second child with the same clinical presentation, his curiosity prompted him to study hospital records for similar cases. He found that these tumors affecting the mandible and maxilla were not unusual [1]. He began to record cases that presented to hospital as well as contacting colleagues throughout sub-Saharan Africa to determine whether or not this characteristic tumor had been observed elsewhere. Colleagues in Kenya, (then) Tanganyika, Nigeria, (then) Belgian Congo, and (then) Rhodesia all confirmed seeing cases similar to the ones he was observing in Uganda. He published these findings in 1958 in the British Journal of Surgery in an article titled ‘‘A sarcoma involving the jaws of African children’’ [2]. In this issue of Pediatric Blood & Cancer, Orem et al. [3] continue Dr. Burkitt’s work by compiling medical records, summarizing their observations, and trying to improve the prognosis of children diagnosed with cancer in Uganda today. Estimates predict that by 2020, the number of new cancer cases will increase by 15 million, with the burden of cancer morbidity and mortality carried by developing countries. By this date, the total number of new cases in developed nations is expected to increase by 29% while the total number of cases in developing countries is expected to increase by 73% [4]. Currently only 5% of all global cancer resources are spent in developing countries [5]. In conjunction with the increase in cases, mortality is estimated to be approximately fivefold greater in economically disadvantaged countries when compared to industrialized nations [6], even though one third of these cancers are preventable and another third are treatable if detected early. Unfortunately, approximately 75% of cancer patients in developing countries are in advanced stages of the disease by the time they reach a health care facility with the capacity to diagnose and treat cancer [7]. In order to increase cancer awareness in Africa, the World Health Organization (WHO) has delineated overarching priorities. This strategy involves cancer prevention, registries, early diagnosis and treatment, and palliative care; including provisions that ‘‘responses should be culturally appropriate, economically feasible, and evidence-based’’ [8]. This renewed global interest parallels increased cancer research conducted in Africa within the context of public health priorities faced by these communities. This is especially true due to the prevalence of AIDS-related lymphomas [9] that did not exist during Denis Burkitt’s tenure in Uganda. For childhood cancer in Africa, the study by Orem et al. [3] was able to analyze an impressive number of medical records that were available from 1994 to 2004 to determine the impact of HIV infection on the response to cytotoxic treatment and prognosis of children with Burkitt lymphoma. This is the first report of its kind and offers clinicians a slight reprieve by demonstrating that children diagnosed with Burkitt lymphoma had similar response rates to chemotherapy irrespective of their HIV status. While the study found that the overall survival in children with HIV was poorer than HIV-seronegative children, these patients were seen prior to the wide-spread rollout of anti-retroviral therapy in Uganda. Unlike in adults, where Burkitt lymphoma is an AIDS-defining malignancy, HIV does not appear to be a risk factor for pediatric Burkitt lymphoma [10]. However, the authors raise the issue that concomitant HIV infection may influence clinical presentation (i.e., tumor site) or rate of tumor progression. Their finding that HIVseropositive children present more commonly with lymphadenopathy was also reported in a study conducted in Malawi [11]. Most HIV-infected children arrived at hospital in advanced stage of disease, which also contributed to poor prognosis. Unlike Kaposi sarcomas, there has not been a dramatic decrease in the incidence of HIV-associated non-Hodgkin lymphomas since the introduction of highly active antiretroviral therapy [12]. These clinicalepidemiologic observations emphasize differences in risk factors and tumorigenesis of AID-defining malignancies and reinforce the need to understand etiologic mechanisms leading to a diagnosis of Burkitt lymphoma. The role of another viral co-infection was described for Burkitt lymphoma in 1964 after the isolation of the Epstein–Barr Virus (EBV) by Drs. Epstein, Barr and Achong from a Ugandan patient tumor sample [13]. After the discovery of EBV as a risk factor, a geographic association with high malaria transmission was mapped for endemic Burkitt lymphoma in Africa [14]. This led to the hypothesis that malaria suppressed immune surveillance to EBV and thereby allowed tumorigenesis. However, malaria is not ‘‘immunosuppressive’’ but rather ‘‘immune-modulating’’ concluded by the fact that children with malaria are not at increased risk for opportunistic infections such as those observed in people

Historical background.

The persisting ancient view of cancer as a contagious disease ended with 19th century scientific investigations which seemed to show it was not. The resulting dogma against an infectious cause for cancer produced great prejudice in the scientific community against the first report of an oncogenic virus by Rous early in the 20th century and, even in the 1950s, against Gross's finding of a murine leukaemia virus and a murine virus causing solid tumours. The Lucké frog renal carcinoma virus was the first cancer-associated herpesvirus. Intriguingly, an environmental factor, ambient temperature, determines virus genome expression in the poikilothermic frog cells. Although an alpha-herpesvirus, Marek's disease virus of chickens shares some aspects of biological behaviour with Epstein-Barr virus (EBV) of man. Very significantly, its lymphomas are the first naturally occurring malignancy to be controlled by an antiviral vaccine, with implications for human virus-associated cancers. The circumstances and climate of opinion in which successive gamma-herpesviruses were discovered are described. The identification of EBV involved two unconventionalities: its finding in cultured Burkitt's lymphoma cells when no human lymphoid cell had ever been maintained in vitro, and its recognition in the absence of biological activity by the then new technique of electron microscopy. These factors engendered hostility to its acceptance as a new human tumour-associated virus. The EBV-like agents of Old World apes and monkeys and the T-lymphotropic gamma-herpesviruses of New World monkeys were found at about the same time, not long after the discovery of EBV. For many years these were thought to be the only gamma-herpesviruses of non-human primates; however, very recently B-lymphotropic EBV-like agents have been identified in New World species as well. Mouse herpesvirus 68 came to light by chance during a search for arboviruses and has become important as a laboratory model because of its close genetic relatedness to EBV and its comparable biological behaviour. The discovery of Kaposi's sarcoma-associated herpesvirus six years ago was made using unconventional new methods, but, unlike with EBV 30 years before, this did not hinder its acceptance. This contrast is discussed in the context of the great progress in human tumour virology which has been made in recent years.

Control of viral disease: the development of Epstein-Barr virus vaccines

Since the discovery of Epstein-Barr virus (EBV) in an African Burkitt 's lymphoma biopsy by M.A. Epstein in 1964 [17], research into the molecular biology and immunology of infection by this virus has grown to be a major field of interest. The association of EBV with two major human cancers, endemic Burkitt 's lymphoma [41] (BL) and undifferentiated nasopharyngeal carcinoma (NPC) [16, 28, 79, 80] led to the proposal for the development of a vaccine to prevent infection by the virus to reduce the incidence of, or to eliminate entirely, cancers associated with EBV infection [15]. The development of EBV vaccines, starting with the conventional subunit type, has closely paralleled developments in DNA technology, adjuvant research and advances in the immunology of EBV. This account describes the development of EBV vaccines in recent years starting with purified envelope glycoproteins as subunit vaccines and extending to live recombinant virus vectors and synthetic peptides. Such has been the progress in this field that Phase I human trials on a recombinant-derived purified envelope glycoprotein subunit vaccine are scheduled for the near future.

Epstein-Barr virus and human diseases: recent advances in diagnosis.

Since the discovery of Epstein-Barr virus (EBV) from a cultured Burkitt's lymphoma cell line in 1964, the virus has been associated with Burkitt's lymphoma, nasopharyngeal carcinoma, and infectious mononucleosis. During the recent decade, EBV has been etiologically implicated in a broad spectrum of human diseases. The precise role of this virus in these diseases is not well understood, but clearly, defective immunosurveillance against the virus may permit an uncontrolled proliferation of EBV-infected cells. As a result, a growing number of cases of EBV-associated B-cell proliferative diseases or lymphoma have been noted in patients with primary and acquired immunodeficiencies. These lymphoproliferative diseases and others, such as chronic mononucleosis syndrome, are leading to new areas of investigation which are providing information regarding the pathogenetic mechanisms of EBV-induced diseases. The early accurate diagnosis of EBV infection can be achieved by performing EBV-specific serology, detecting for EBV-determined nuclear antigen in tissues, establishing spontaneous lymphoid cell lines, and using molecular hybridization techniques for demonstrating the presence of viral genome in affected lesions.

Epstein-Barr virus and human diseases: recent advances in diagnosis.

Since the discovery of Epstein-Barr virus (EBV) from a cultured Burkitt's lymphoma cell line in 1964, the virus has been associated with Burkitt's lymphoma, nasopharyngeal carcinoma, and infectious mononucleosis. During the recent decade, EBV has been etiologically implicated in a broad spectrum of human diseases. The precise role of this virus in these diseases is not well understood, but clearly, defective immunosurveillance against the virus may permit an uncontrolled proliferation of EBV-infected cells. As a result, a growing number of cases of EBV-associated B-cell proliferative diseases or lymphoma have been noted in patients with primary and acquired immunodeficiencies. These lymphoproliferative diseases and others, such as chronic mononucleosis syndrome, are leading to new areas of investigation which are providing information regarding the pathogenetic mechanisms of EBV-induced diseases. The early accurate diagnosis of EBV infection can be achieved by performing EBV-specific serology, detecting for EBV-determined nuclear antigen in tissues, establishing spontaneous lymphoid cell lines, and using molecular hybridization techniques for demonstrating the presence of viral genome in affected lesions.