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BackgroundMore than 90% of the adult population globally is chronically infected by the Epstein–Barr virus (EBV). It is well established that EBV is associated with a number of malignancies, and advances in knowledge of EBV-related malignancies are being made every year. Several studies have analysed the global epidemiology and geographic distribution of EBV-related cancers. However, most have only described a single cancer type or subtype in isolation or limited their study to the three or four most common EBV-related cancers. This review will present an overview on the spectrum of cancers linked to EBV based on observations of associations and proportions in the published literature while also using these observations to estimate the incidence and mortality burden of some of these cancers.MethodWe have reviewed the literature on defining features, distribution and outcomes across six cancers with a relatively large EBV-related case burden: Nasopharyngeal carcinoma (NPC), Gastric carcinoma (GC), Hodgkin lymphoma (HL), Burkitt lymphoma (BL), Diffuse large B-cell lymphoma (DLBCL) and Extranodal NK/T-cell lymphoma, Nasal type (ENKTL-NT). We retrieved published region-specific EBV-related case proportions for NPC, GC, HL and BL and performed meta-analyses on pooled region-specific studies of EBV-related case proportions for DLBCL and ENKTL-NT. We match these pooled proportions with their respective regional incidence and mortality numbers retrieved from a publicly available cancer database. Additionally, we also reviewed the literature on several other less common EBV-related cancers to summarize their key characteristics herein.ConclusionWe estimated that EBV-related cases from these six cancers accounted for 239,700–357,900 new cases and 137,900–208,700 deaths in 2020. This review highlights the significant global impact of EBV-related cancers and extends the spectrum of disease that could benefit from an EBV-specific therapeutic.

EBV is a prevalent virus, infecting >90% of the world’s population. This is an oncogenic virus that causes ~200,000 cancer-related deaths annually. It is, in addition, a significant contributor to the burden of autoimmune diseases. Thus, EBV represents a significant public health burden. Upon infection, EBV remains dormant in host cells for long periods of time. However, the presence or episodic reactivation of the virus increases the risk of transforming healthy cells to malignant cells that routinely escape host immune surveillance or of producing pathogenic autoantibodies. Cancers caused by EBV display distinct molecular behaviors compared to those of the same tissue type that are not caused by EBV, presenting opportunities for targeted treatments. Despite some encouraging results from exploration of vaccines, antiviral agents and immune- and cell-based treatments, the efficacy and safety of most therapeutics remain unclear. Here, we provide an up-to-date review focusing on underlying immune and environmental mechanisms, current therapeutics and vaccines, animal models and emerging technologies to study EBV-associated diseases that may help provide insights for the development of novel effective treatments.

Epstein–Barr virus (EBV) is a ubiquitous virus detected in up to 95% of the general population. Most people are asymptomatic, while some may develop a wide range of EBV-associated lymphoproliferative disorders (LPD). Among them, EBV-positive T/NK LPD are uncommon diseases defined by the proliferation of T- or NK-cells infected by EBV. The 2017 World Health Organization (WHO) classification recognizes the following entities characterized by different outcomes: chronic active EBV infection of T- or NK-cell types (cutaneous and systemic forms), systemic EBV-positive T-cell lymphoma of childhood, EBV-positive aggressive NK-cell leukemia, extra nodal NK/T-cell lymphoma nasal type, and the new provisional entity known as primary EBV-positive nodal T/NK-cell lymphoma. In addition, EBV associated-hemophagocytic lymphohistiocytosis is part of EBV-positive T/NK LPD, but has not been included in the WHO classification due to its reactive nature. Despite novel insights from high-throughput molecular studies, EBV-positive NK/T-cell LPD diagnoses remain challenging, especially because of their rarity and overlap. Until now, an accurate EBV-positive NK/T LPD diagnosis has been based on its clinical presentation and course correlated with its histological features. This review aims to summarize clinical, pathological and molecular features of EBV-positive T/NK LPD subtypes and to provide an overview of new understandings regarding these rare disorders.

Background. University students were studied prospectively to determine the incidence of and risk factors for acquisition of primary Epstein-Barr virus (EBV) infection and the virologic and immune correlates of disease severity. Methods. EBV antibody-negative freshmen participated in monthly surveillance until graduation. If antibodies developed, proximate samples were assayed for viral load by polymerase chain reaction. Lymphocyte and natural killer (NK) cell numbers and activation were measured by flow cytometry, and plasma cytokine levels were measured by a multiplex assay. Results. Of 546 students screened, 202 (37%) were antibody negative; 143 antibody-negative students were enrolled. During a median of 3 years of observation, 66 subjects experienced primary infection. Of these, 77% had infectious mononucleosis, 12% had atypical symptoms, and 11% were asymptomatic. Subjects reporting deep kissing with or without coitus had the same higher risk of infection than those reporting no kissing (< .01). Viremia was transient, but median oral shedding was 175 days. Increases were observed in numbers of NK cells and CD8⁺ T-cells but not in numbers of CD4⁺ T-cells during acute infection. Severity of illness correlated positively with both blood EBV load (P = .015) and CD8⁺ lymphocytosis (P = .0003). Conclusions. Kissing was a significant risk for primary EBV infection. A total of 89% of infections were symptomatic, and blood viral load and CD8⁺ lymphocytosis correlated with disease severity.

Using Epstein‐Barr virus (EBV)‐induced cancer cells and HeLa cells as a comparative study model, a novel and safe dual‐EBV‐oncoproteins‐targeting pH‐responsive peptide engineering, coating, and guiding approach to achieve precision targeting and treatment strategy against EBV‐associated cancers is introduced. Individual functional peptide sequences that specifically bind to two overexpressed EBV‐specific oncoproteins, EBNA1 (a latent cellular protein) and LMP1 (a transmembrane protein), are engineered in three different ways and incorporated with a pH‐sensitive tumor microenvironment (TME)‐cleavable linker onto the upconversion nanoparticles (UCNP) NaGdF4:Yb3+, Er3+@NaGdF4 (UCNP‐Pn, n = 5, 6, and 7). A synergistic combination of the transmembrane LMP1 targeting ability and the pH responsiveness of UCNP‐Pn is found to give specific cancer differentiation with higher cellular uptake and accumulation in EBV‐infected cells, thus a lower dose is needed and the side effects and health risks from treatment would be greatly reduced. It also gives responsive UC signal enhancement upon targeted dual‐protein binding and shows efficacious EBV cancer inhibition in vitro and in vivo. This is the first example of simultaneous imaging and inhibition of two EBV latent proteins, and serves as a blueprint for next‐generation peptide‐guided precision delivery nanosystem for the safe monitoring and treatment against one specific cancer. The upconversion nanoplatform with desired responsiveness toward tumor microenvironment is introduced. Thereafter, EBV‐cancer model is used to investigate by utilizing the safe nanoplatform via targeting LMP1 and EBNA1 with responsive emission, satisfactory prohibitive performances are observed in vitro and in vivo, thanks to the specific dual‐targeting peptides. This proposed multifunctional nanoplatform can achieve both monitoring and treatment for EBV cancer.

Epstein-Barr virus (EBV) is the first human tumor virus discovered and is strongly implicated in the etiology of multiple lymphoid and epithelial cancers. Each year EBV associated cancers account for over 200,000 new cases of cancer and cause 150,000 deaths world-wide. EBV is also the primary cause of infectious mononucleosis, and up to 70% of adolescents and young adults in developed countries suffer from infectious mononucleosis. In addition, EBV has been shown to play a critical role in the pathogenesis of multiple sclerosis. An EBV prophylactic vaccine that induces neutralizing antibodies holds great promise for prevention of EBV associated diseases. EBV envelope proteins including gH/gL, gB and gp350 play key roles in EBV entry and infection of target cells, and neutralizing antibodies elicited by each of these proteins have shown to prevent EBV infection of target cells and markedly decrease EBV titers in the peripheral blood of humanized mice challenged with lethal dose EBV. Recent studies demonstrated that immunization with the combination of gH/gL, gB and/or gp350 induced markedly increased synergistic EBV neutralizing activity compared to immunization with individual proteins. As previous clinical trials focused on gp350 alone were partially successful, the inclusion of gH/gL and gB in a vaccine formulation with gp350 represents a promising approach of EBV prophylactic vaccine development. Therapeutic EBV vaccines have also been tested clinically with encouraging results. Immunization with various vaccine platforms expressing the EBV latent proteins EBNA1, LMP1, and/or LMP2 promoted specific CD4+ and CD8+ cytotoxic responses with anti-tumor activity. The addition of EBV envelope proteins gH/gL, gB and gp350 has the potential to increase the efficacy of a therapeutic EBV vaccine. The immune system plays a critical role in the control of tumors, and immune cell therapy has emerged as a promising treatment of cancers. Adoptive T-cell therapy has been successfully used in the prevention and treatment of post-transplant lymphoproliferative disorder. Chimeric antigen receptor T cell therapy and T cell receptor engineered T cell therapy targeting EBV latent proteins LMP1, LMP2 and/or EBNA1 have been in development, with the goal to increase the specificity and efficacy of treatment of EBV associated cancers.

Prophylactic vaccines against Epstein–Barr virus (EBV) are under development. EBV-naïve college freshmen are ideal candidates for an efficacy trial, because their incidence of infectious mononucleosis (mono) during freshman year is as high as 20%. To assess perceptions about mono and a mono vaccine, and to learn if EBV immune status could be determined using a gingival swab rather than phlebotomy, we performed a cross-sectional study of 235 healthy students at the beginning of their freshman year. Subjects completed questionnaires and donated oral washes, gingival swabs and venous blood. Overall, 90% of students found the swab easy to use and 80% preferred the swab over venepuncture. Of the 193 students with sufficient samples, 108 (56%) had EBV antibodies in blood vs. 87 (45.1%) in the gingival swab. The sensitivity and specificity of the swab compared with blood for detecting EBV antibodies was 75.9% and 94.1%, respectively, with an accuracy of 89.3%. EBV DNA was detected in the oral wash and swab of 39.2% and 30.4% of blood-antibody-positive individuals, respectively. In conclusion, 44% of our freshmen were EBV-naïve and thus vaccine candidates, the gingival swab was an acceptable alternative to phlebotomy for detecting EBV antibody but needs improved sensitivity, and the perceived value of EBV vaccine was high (72% believed they would benefit).

Background. Data on the age-specific prevalence of Epstein-Barr virus (EBV) infection are relevant for determining when to administer a prophylactic vaccine. Comparison of demographic groups could identify factors associated with its acquisition. Methods. The National Health and Nutrition Examination Surveys (NHANES) examine a representative sample of the US population. Serum specimens from NHANES participants 6-19 years old were tested for EBV antibody by enzyme immunoassay (EIA). A random portion was also tested by indirect immunofluorescence (IFA). Prevalence estimates and risk-factor comparisons used demographic data and sampling weights in logistic regression models. Results. Serum specimens collected between 2003 and 2010 from 9338 individuals participating in NHANES were tested. The concordance between EIA and IFA findings was 96.7%. The overall age-adjusted EBV antibody prevalence declined from 72% in 2003-2004 to 65% in 2009-2010 (P= .027). The prevalence in 2009-2010 by age group was as follows: 6-8 years, 50%; 9-11 years, 55%; 12-14 years, 59%; 15-17 years, 69%; and 18-19 years, 89%. Within each race/ethnicity group, younger age, health insurance coverage, higher household income, and education level were significantly associated with a lower prevalence of EBV antibody. Conclusions. The EBV antibody prevalence declined in US individuals aged 6-19 years from 2003-2004 to 2009-2010, mainly because of the decrease among non-Hispanic white participants. The declining antibody prevalence over time and the consistently high observed prevalence among participants aged 12-19 years support broad use of EBV vaccine before 12 years of age.

Chronic active Epstein–Barr virus (EBV) infection (CAEBV) is a rare syndrome characterized by prolonged infectious mononucleosis-like symptoms and elevated peripheral blood EBV DNA load in apparently immunocompetent persons. CAEBV has been primarily reported in East Asia and Latin America, suggesting a genetic predisposition in its pathogenesis. In most cases of CAEBV, EBV induces proliferation of its unusual host cells, T or natural killer (NK) cells. The clinical course of CAEBV is heterogeneous; some patients show an indolent course, remaining in a stable condition for years, whereas others show an aggressive course with a fatal outcome due to hemophagocytic lymphohistiocytosis, multiple organ failure, or progression to leukemia/lymphoma. The pathogenesis of CAEBV is unclear and clinicopathological investigations suggest that it has aspects of both malignant neoplasm and immunodeficiency. Recent genetic analyses of both viral and host genomes in CAEBV patients have led to discoveries that are improving our understanding of the nature of this syndrome. This article summarizes the latest findings on CAEBV and discusses critical unsolved questions regarding its pathogenesis and disease concept.

Epstein–Barr virus (EBV) was discovered in 1964 in the cell line of Burkitt lymphoma and became first known human oncogenic virus. EBV belongs to the Herpesviridae family, and is present worldwide as it infects 95% of people. Infection with EBV usually happens during childhood when it remains asymptomatic; however, in adults, it can cause an acute infection known as infectious mononucleosis. In addition, EBV can cause wide range of tumors with origins in B lymphocytes, T lymphocytes, and NK cells. Its oncogenicity and wide distribution indicated the need for vaccine development. Research on mice and cultured cells as well as human clinical trials have been in progress for a few decades for both prophylactic and therapeutic EBV vaccines. The main targets of the vaccines are EBV envelope glycoproteins such as gp350 and EBV latent genes. The long wait for the EBV vaccine is due to the complexity of the EBV replication cycle and the wide range of its host cells. Although some strategies such as the use of dendritic cells and recombinant Vaccinia viral vectors have shown success, ongoing clinical trials using mRNA-based vaccines as well as new delivery systems as nanoparticles are yet to show the best choice of vaccine target and its production strategy.