Search Results (44)

Background and Objectives: Primary Epstein–Barr virus (EBV) infection in pediatric kidney transplant recipients with donor/recipient mismatch (D+/R−) carries the highest risk of post-transplant lymphoproliferative disorder (PTLD). Current prophylactic strategies are not standardized. Intravenous immunoglobulins (IVIG), containing anti-EBV antibodies, have been proposed as a potential preventive option, but evidence is lacking. This single-center retrospective case–control study evaluated the efficacy of serial IVIG administration in preventing primary EBV infection and promoting long-term immunity in this high-risk population. Materials and Methods: We retrospectively analyzed 26 pediatric kidney transplant recipients (age 1–18 years) with EBV D+/R− mismatch and a median follow-up of 7.5 years. Fourteen patients received scheduled IVIG infusions (200 mg/kg monthly for six months post-transplantation), while twelve received no EBV-directed prophylaxis. The primary endpoint was the cumulative incidence of primary EBV infection, defined as EBV-DNA > 1000 copies/mL in peripheral blood. The secondary endpoint was Epstein–Barr Nuclear Antigen-Immunoglobulin G (EBNA-IgG) seroconversion. Results: Patients receiving IVIG were significantly younger than controls (median age 4.2 vs. 10.8 years, p = 0.01). No significant variations were observed between groups in renal function or immunosuppressive levels during follow-up. IVIG prophylaxis was unexpectedly linked to a higher cumulative incidence of EBV infection compared with controls (64% vs. 25%, p = 0.047). Time-to-event analysis confirmed an increased, although not statistically significant, risk of EBV acquisition in the IVIG group (Hazard Ratio [HR] 3.24, 95% Confidence Interval [CI] 0.87–12.01; p = 0.079). EBV-specific immunity, assessed by EBNA-IgG seroconversion, was comparable between groups (HR 1.78; p = 0.45), confirming no immunological advantage of IVIG. One IVIG-treated patient (7.1%) developed PTLD, while none did in the control group. Conclusions: Scheduled IVIG administration during the first six months after transplantation does not constitute an effective strategy to prevent primary EBV infection or to enhance long-term immunity in high-risk EBV D+/R− pediatric kidney recipients and may even increase susceptibility to viral acquisition. These findings argue against the use of IVIG as EBV prophylaxis in this population. Full article

This study aimed to explore the intricate relationship between mitochondrial dysfunction, infection, and neuroinflammation, focusing specifically on the impact of pathogenic epitopes of the Epstein–Barr Virus (EBV) nuclear antigen 1 (EBNA1) in a mouse model of mitochondrial dysfunctions. The investigation included female middle-aged PARK2^−/− and C57BL/6J wild-type mice immunized with EBNA1_386–405 or with active experimental autoimmune encephalomyelitis (EAE) induction by the myelin oligodendrocyte glycoprotein (MOG)_35–55 peptide. The PARK2^−/− mice developed more severe EAE than the wild-type mice. Following immunization with EBNA1_386–405, only PARK2^−/− exhibited symptoms resembling EAE. During the acute phase, PARK2^−/− mice immunized with either MOG_35–55 or EBNA1_386–405 exhibited a similar infiltration of the T cells and macrophages in the spinal cord and decreased glial fibrillary acidic protein (GFAP) expression in the brain. However, the EBNA1_386–405 -immunized PARK2^−/− mice showed significantly increased frequencies of CD8a⁺ T cells and CD11c⁺ B cells, and distinct cytokine profiles in the periphery compared to the wild-type controls. These findings highlight the role of EBV in exacerbating inflammation, particularly in the context of mitochondrial deficiencies. Full article

The Herpesviridae include the Epstein–Barr Virus (EBV) and the Kaposi Sarcoma-associated Herpesvirus (KSHV), both of which are oncogenic gamma-herpesviruses. These viruses manipulate host cellular mechanisms, including through ubiquitin-mediated pathways, to promote viral replication and oncogenesis. Ubiquitin, a regulatory protein which tags substrates for degradation or alters their function, is manipulated by both EBV and KSHV to facilitate viral persistence and cancer development. EBV infects approximately 90% of the global population and is implicated in malignancies including Burkitt lymphoma (BL), Hodgkin lymphoma (HL), post-transplant lymphoproliferative disorder (PTLD), and nasopharyngeal carcinoma. EBV latency proteins, notably LMP1 and EBNA3C, use ubiquitin-mediated mechanisms to inhibit apoptosis, promote cell proliferation, and interfere with DNA repair, contributing to tumorigenesis. EBV’s lytic proteins, including BZLF1 and BPLF1, further disrupt cellular processes to favor oncogenesis. Similarly, KSHV, a causative agent of Kaposi’s Sarcoma and lymphoproliferative disorders, has a latency-associated nuclear antigen (LANA) and other latency proteins that manipulate ubiquitin pathways to degrade tumor suppressors, stabilize oncogenic proteins, and evade immune responses. KSHV’s lytic cycle proteins, such as RTA and Orf64, also use ubiquitin-mediated strategies to impair immune functions and promote oncogenesis. This review explores the ubiquitin-mediated interactions of EBV and KSHV proteins, elucidating their roles in viral oncogenesis. Understanding these mechanisms offers insights into the similarities between the viruses, as well as provoking thought about potential therapeutic targets for herpesvirus-associated cancers. Full article

Background: Epstein–Barr virus (EBV) is involved in the development of lymphomas, nasopharyngeal carcinomas (NPC), and a subgroup of gastric carcinomas (GC), and has also been detected in lung carcinomas, even though the role of the virus in this malignancy has not yet been established. BamH1-A Rightward Frame 1 (BARF1), a suggested exclusive epithelial EBV oncoprotein, is detected in both EBV-associated GCs (EBVaGC) and NPC. The expression and role of BARF1 in lung cancer is unknown. Methods: A total of 158 lung carcinomas including 80 adenocarcinomas (AdCs) and 78 squamous cell carcinomas (SQCs) from Chilean patients were analyzed for EBV presence via polymerase chain reaction (PCR), Immunohistochemistry (IHC), or chromogenic in situ hybridization (CISH). The expression of BARF1 was evaluated using Reverse Transcription Real-Time PCR (RT-qPCR). Additionally, A549 and BEAS-2B lung epithelial cells were transfected with a construct for ectopic BARF1 expression. Cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) were evaluated. Results: We found that EBV was present in 37 out of 158 (23%) lung carcinomas using PCR. Considering EBV-positive specimens using PCR, IHC for Epstein–Barr nuclear antigen 1 (EBNA1) detected EBV in 24 out of 30 (80%) cases, while EBERs were detected using CISH in 13 out of 16 (81%) cases. Overall, 13 out of 158 (8%) lung carcinomas were shown to be EBV-positive using PCR/IHC/CISH. BARF1 transcripts were detected in 6 out of 13 (46%) EBV-positive lung carcinomas using RT qPCR. Finally, lung cells ectopically expressing BARF1 showed increased migration, invasion, and EMT. Conclusions. EBV is frequently found in lung carcinomas from Chile with the expression of BARF1 in a significant subset of cases, suggesting that this viral protein may be involved in EBV-associated lung cancer progression. Full article

Nasopharyngeal carcinoma (NPC) is closely linked to Epstein–Barr virus (EBV) infection. Curcumae Rhizoma, a traditional Chinese herb, has shown antitumor effects, primarily through its component curcumol (Cur), which has been shown to reduce NPC cell invasion and migration by targeting nucleolin (NCL) and Epstein–Barr Virus Nuclear Antigen 1 (EBNA1). We constructed an EBV-positive NPC cell model using C666-1 cells and performed transcriptomics studies after treatment with curcumol, which revealed a significant enrichment of ubiquitin-mediated proteolysis, the PI3K-AKT and mTOR signaling pathways, cell cycle and apoptosis involved in tumor invasion and migration. To investigate the importance of NCL and EBNA1 in curcumol-resistant EBV-positive NPC, we performed a multi-omics study using short hairpin NCL (shNCL) and shEBNA1 EBV-positive NPC cells, and the proteomics results showed enrichment in complement and coagulation cascades and ubiquitin-mediated proteolysis signaling pathways. Here, we focused on ubiquitin-conjugating enzyme E2C (UBE2C), which plays an important role in the ubiquitin-mediated proteolysis signaling pathway. In addition, metabolomics revealed that UBE2C is highly associated with 4-Aminobutanoic acid (GABA). In vitro studies further validated the function of the key targets, suggesting that UBE2C plays an important role in NCL and EBNA1-mediated curcumol resistance to nasopharyngeal carcinoma invasion and metastasis. Full article

Epstein–Barr virus (EBV), a member of the γ-herpesvirus family, is one of the most prevalent and persistent human viruses, infecting up to 90% of the adult population globally. EBV’s life cycle includes primary infection, latency, and lytic reactivation, with the virus primarily infecting B cells and epithelial cells. This virus has evolved sophisticated strategies to evade both innate and adaptive immune responses, thereby maintaining a lifelong presence within the host. This persistence is facilitated by the expression of latent genes such as EBV nuclear antigens (EBNAs) and latent membrane proteins (LMPs), which play crucial roles in viral latency and oncogenesis. In addition to their well-known roles in several types of cancer, including nasopharyngeal carcinoma and B-cell lymphomas, recent studies have identified the pathogenic roles of EBV in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. This review highlights the intricate interactions between EBV and the host immune system, underscoring the need for further research to develop effective therapeutic and preventive strategies against EBV-associated diseases. Full article

Epstein–Barr virus (EBV) infection and various chemokines, including CCL20, CXCL8 and CXCL10 are considered to participate in the pathogenesis of multiple sclerosis (MS), and several studies point to a direct regulatory effect of EBV on the expression of these chemokines. In our study we hypothesized that serum concentrations of CCL20, CXCL8 and CXCL0 are induced in patients with relapsing-remitting MS (RRMS) in comparison to healthy individuals, and that they are associated with EBV infection. Serum concentrations of CXCL8 and CXCL10 were lower in RRMS patients in relapse in comparison to healthy controls. Although potential effects of corticosteroid therapy introduced in a subgroup of RRMS patients prior to sampling were excluded by subgroup comparison, this possibility has to be considered while interpreting the results. We found an inverse association between serum concentrations of CXCL8 and anti-Epstein–Barr Virus Nuclear Antigen (EBNA) IgG and decreased expression of CXCL8 in peripheral blood mononuclear cells (PBMC) in relapse compared to remission. Lower serum concentrations of CXCL8 and CXCL10 in RRMS patients and decreased peripheral production of CXCL8 in relapse may indicate compensatory anti-inflammatory counter-regulation in MS. Full article

Cervical cancer is the fourth most diagnosed cancer and the fourth leading cause of cancer death in women globally. Its onset and progression have been attributed to high-risk human papillomavirus (HPV) types, especially 16 and 18, while the Epstein–Barr virus (EBV) is believed to also significantly contribute to cervical cancer growth. The E6 protein associated with high-risk HPV strains, such as HPV16 and HPV18, is known for its role in promoting cervical cancer and other anogenital cancers. E6 proteins contribute to the malignant transformation of infected cells by targeting and degrading tumor suppressor proteins, especially p53. On the other hand, EBV nuclear antigen 1 (EBNA1) plays a crucial role in the maintenance and replication of the EBV genome in infected cells. EBNA1 is believed to increase HPV E6 and E7 levels, as well as c-MYC, and BIRC5 cellular genes in the HeLa cell line, implying that HPV/EBV co-infection accelerates cervical cancer onset and growth. Thus, the E6 and EBNA1 antigens of HPV and EBV, respectively, are attractive targets for cervical cancer immunotherapy. This study, therefore, virtually screened for potential drug candidates with good binding affinity to all three oncoviral proteins, HPV16 E6, HPV18 E6, and EBNA1. The compounds were further subjected to ADMET profiling, biological activity predictions, molecular dynamics (MD) simulations, and molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) calculations. A total of six compounds comprising ZINC000013380012, ZINC000070454124, ZINC000014588133, ZINC000085568136, ZINC000095909247, and ZINC000085597263 demonstrated very strong affinity (≤−60 kJ/mol) to the three oncoviral proteins (EBNA1, HPV16 E6, and HPV18 E6) after being subjected to docking, MD, and MM/PBSA. These compounds demonstrated relatively stronger binding than the controls used, inhibitors of EBNA1 (VK-1727) and HPV E6 (baicalein and gossypetin). Biological activity predictions also corroborated their antineoplastic, p53-enhancing, Pin1 inhibitory, and JAK2 inhibitory activities. Further experimental testing is required to validate the ability of the shortlisted compounds to silence the insidious effects of HPV E6 and EBNA1 proteins in cervical cancers. Full article

Induced pluripotent stem cells (iPSCs) are a powerful tool for biomedical research, but their production presents challenges and safety concerns. Yamanaka and Takahashi revolutionised the field by demonstrating that somatic cells could be reprogrammed into pluripotent cells by overexpressing four key factors for a sufficient time. iPSCs are typically generated using viruses or virus-based methods, which have drawbacks such as vector persistence, risk of insertional mutagenesis, and oncogenesis. The application of less harmful nonviral vectors is limited as conventional plasmids cannot deliver the levels or duration of the factors necessary from a single transfection. Hence, plasmids that are most often used for reprogramming employ the potentially oncogenic Epstein–Barr nuclear antigen 1 (EBNA-1) system to ensure adequate levels and persistence of expression. In this study, we explored the use of nonviral SMAR DNA vectors to reprogram human fibroblasts into iPSCs. We show for the first time that iPSCs can be generated using nonviral plasmids without the use of EBNA-1 and that these DNA vectors can provide sufficient expression to induce pluripotency. We describe an optimised reprogramming protocol using these vectors that can produce high-quality iPSCs with comparable pluripotency and cellular function to those generated with viruses or EBNA-1 vectors. Full article

Prostate cancer (PCa) is the fourth most frequently diagnosed cancer worldwide, accounting for 7.3% of all cancers. PCa mortality is the fifth most common cause of cancer death. Despite well-known factors influencing the development of PCa, such as age, race/ethnicity and family history, many researchers have raised the possibility of persistent infections with oncogenic viruses. Therefore, we aimed to assess the frequency of Epstein–Barr virus (EBV) DNA in tissue collected from PCa patients. Next, the frequency and the level of Epstein–Barr virus capsid antigen (EBVCA) and Epstein–Barr nuclear antigen 1 (EBNA1) antibodies in both IgA and IgG classes were measured. The antibody titer was also analyzed depending on the risk group, Gleason score (GS) and tumor, node, metastasis (TNM) classification. Serum samples were analyzed using the Microblot-Array EBV IgM, IgA and IgG test kits. The study group consisted of 115 patients diagnosed and histopathologically confirmed with PCa. In 49% of patients included in the study, EBV DNA was detected in the tumor tissue. The studies showed both higher seroprevalence and higher antibody titers in patients with EBV-positive PCa compared to patients with EBV-negative PCa. We also observed a dependence of antibody titer on pathological features, such as GS, risk group and T stage. Full article

Multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocytes glycoprotein-antibody disease (MOGAD) are distinct autoimmune demyelinating disorders characterized by varying clinical and pathological characteristics. While the precise origins of these diseases remain elusive, a combination of genetic and environmental factors, including viral elements, have been suggested as potential contributors to their development. Our goal was to assess the occurrence of antibodies against pathogenic peptides associated with Epstein–Barr virus (EBV) and the human endogenous retrovirus-W (HERV-W) in serum samples obtained from Japanese individuals diagnosed with MS, NMOSD, and MOGAD and to make comparisons with a group of healthy controls (HCs). We conducted a retrospective analysis involving 114 Japanese participants, comprising individuals with MS (34), NMOSD (20), MOGAD (20), and HCs (40). These individuals were tested using a peptide-based enzyme-linked immunosorbent assay. A marked increase in antibody response against EBV nuclear antigen 1 (EBNA1)_386–405 was observed in the serum of MS and MOGAD patients, as compared to HCs. Notably, we observed a correlation between antibodies against EBNA1_386–405 and HERV-W_486–504 peptides in a subset of the antibody-positive MS patients. These findings emphasize the involvement of EBV in the pathogenesis of MS and potentially MOGAD, suggesting its role in the reactivation of HERV-W. Full article

Based on epidemiological evidence and molecular findings, a possible association of Epstein–Barr virus (EBV) with the carcinogenesis of breast cancer has been described. However, the frequency of EBV in breast cancer and the role of EBV regarding tumor progression or therapeutic results is largely unexplored. Here, we report on two cases of advanced, lymph node-positive invasive breast cancer of no special type (NST), histologically showing no clinical or histological evidence of tumor regression as an equivalent of a lack of response to primary systemic therapy. Both tumors were considered to be EBV-associated due to their positivity in EBV-encoded RNA (EBER) in situ hybridization (ISH) and their immunoreactivity against EBV Epstein–Barr nuclear antigen 1 (EBNA1). We hypothesize that the unusual non-response to chemotherapy in these cases of breast cancer classified as triple-negative and HER2-positive may be linked to the EBV co-infection of tumor cells. Therefore, EBV tumor testing should be considered in patients with breast cancer presenting with resistance to chemotherapy. This hypothesis may provide a new aspect in the context of EBV-associated mechanisms of tumor progression. Full article

Chronic active Epstein–Barr virus (EBV) infection (CAEBV) is characterized by chronic or recurrent infectious mononucleosis-like symptoms and is associated with EBV-associated T/natural killer (NK)-cell lymphoproliferative disorders, which frequently lead to the development of life-threatening complications, such as virus-associated hemophagocytic syndrome and EBV-positive apparent leukemia/lymphoma mainly in T- and NK-cell lineages. In order to clarify the EBV genes responsible for the diseases, we introduced the plasmid coding sequences of EBV-encoded small RNAs (EBERs) and/or latent membrane protein (LMP) 1 into human T-lymphocyte virus-I-negative human T-cell lines using a gene expression vector harboring EBV nuclear antigen 1, established the G418-resistant transformants of five T-cell lines, and quantitatively examined the expression of EBERs and LMP1 using real-time reverse transcriptase–polymerase chain reaction. The expression levels of EBERs in T-cell transformants with EBER DNA paralleled those in EBV-positive human T- and NK-cell lines, SNTK cells. The expression of LMP1 mRNA varied in SNTK cells and in human T-cell transformants, and the expression of LMP1 mRNA in T-cell lines expressing both EBERs and LMP1 was much lower than that in the same cell line expressing LMP1 mRNA alone. The currently employed gene expression system and currently obtained transformants may be useful for the analyses of the pathophysiology of CAEBV and EBV-positive T/NK-cell lymphoproliferative disorders. Full article

Epstein–Barr virus (EBV) is an oncogenic herpes virus associated with several human malignancies. Two main EBV genotypes (type 1 and type 2) distinguished by the differences in EBV nuclear antigens are known. Geographic variability in these genetic differences has been observed in the incidence of some EBV-related tumors. Here, we investigated the genetic variation of EBV in lymphoma specimens collected in Ethiopia. A total of 207 DNA samples were used for EBV detection and typing, and EBNA1 and EBNA3C genes were used to detect and subtype the EBV genome, respectively. EBV genotype 1 was detected in 52.2% of lymphoma patients. EBV genotype 2 was detected in 38.2% of the lymphoma patients, and 9.7% were coinfected by both EBV genotypes. Overall, 52.8% of the Hodgkin’s lymphoma (HL) patients and 51.8% of non-Hodgkin’s lymphoma (NHL) patients showed the presence of genotype 1. Meanwhile, 42.8% and 2.3% of HL patients and 35.8% and 12.4% of NHL patients showed EBV genotype 2 and both genotypes, respectively. Significant associations between the age groups and EBV genotypes were observed (p = 0.027). However, no significant association was seen between EBV genotypes and other sociodemographic and clinical characteristics. This study showed that the distribution of EBV genotype 1 was higher in Ethiopian lymphoma patients. Full article

Although the connection between Epstein–Barr virus (EBV) and rheumatoid arthritis (RA) has been studied for over 40 years, many questions still need clarification. The study aimed to analyze the possible association between anti-EBV antibody titers, EBV DNA viremia, EBV infection status and EBNA1 (Epstein–Barr nuclear antigen 1—EBNA1) variants and clinical parameters of RA patients. This prospective cohort study included 133 RA patients and 50 healthy controls. Active/recent EBV infection was more prevalent in RA patients than in controls (42% vs. 16%, p < 0.001). RA patients had higher titers of anti-EBV-CA-IgM (capsid antigen—CA) and anti-EBV-EA(D)-IgG (early antigen—EA) antibodies than controls (p = 0.003 and p = 0.023, respectively). Lower levels of anti-EBNA1-IgG and anti-EBV-CA-IgG were observed in RA patients who received methotrexate (anti-EBNA1 IgG p < 0.001; anti-EBV-CA IgG p < 0.001). Based on amino acid residue on position 487, two EBNA1 prototypes were detected: P-Thr and P-Ala. Patients with active/recent EBV infection had a five times more chance of having RA and a nearly six times more chance of getting RA. Also, EBV active/recent infection is twice more likely in newly diagnosed than in methotrexate-treated patients. Further studies are needed to clarify “who is the chicken and who is the egg” in this EBV–RA relationship. Full article