RESUMEN
INTRODUCTION: Epstein-Barr virus (EBV) infection, with a global prevalence exceeding 95%, typically manifests in children as infectious mononucleosis. However, clinical practice frequently encounters diverse atypical presentations characterized by multisystem involvement, often resulting in an unfavorable clinical course. Our objective is to describe the clinical manifestations and results of EBV infection in a tertiary pediatric hospital in Mexico. METHOD: An observational, transversal, retrospective, and descriptive study that included a systematic review of medical records (2012-2022) of patients under 18 years of age with detectable EBV particles in peripheral blood. RESULTS: The study included 26 patients with a median age of 5 years and a male predominance of 53.8%. Predominant symptoms were fever (85%) and lymphadenopathy (35%). Sixty-five percent had severe and atypical manifestations, including pneumonia and hepatic, hematologic-oncologic, and autoimmune diseases. Anemia, thrombocytopenia and leukopenia were common, with lymphocytosis in 19% of cases. The median EBV viral load was 2816 copies/mL (range: 555-355,500 copies/mL). Four deaths related to EBV infection were reported. Viral load in these cases also varied widely from 594 to 121,000 copies/mL. Supportive care was administered to 85% of patients, while others received antiviral treatment, steroids, and rituximab. CONCLUSION: Atypical manifestations were common, especially in children with multisystem involvement. EBV should be considered as a potential contributor to a diverse spectrum of clinical presentations, emphasizing the need for comprehensive evaluation and awareness in clinical diagnosis.
INTRODUCCIÓN: La infección por el virus de Epstein-Barr (VEB) tiene una prevalencia mundial superior al 95%. Se considera que en los niños se manifiesta principalmente como mononucleosis infecciosa; sin embargo, en la práctica clínica, a menudo encontramos numerosas manifestaciones atípicas con compromiso multisistémico que llevan a un curso desfavorable. Nuestro objetivo es describir las manifestaciones clínicas y los resultados de la infección por VEB en un hospital pediátrico de tercer nivel en México. MÉTODO: Estudio observacional, transversal, retrospectivo y descriptivo, en el cual se revisaron sistemáticamente los expedientes médicos de pacientes menores de 18 años con una detección positiva de partículas de VEB en sangre periférica en el periodo 2012-2022. RESULTADOS: Se incluyeron 26 pacientes con una mediana de edad de 5 años y predominio de varones (53.8%). El 65% presentaron manifestaciones graves y atípicas, incluyendo enfermedades respiratorias, hepáticas, hematooncológicas y autoinmunitarias. Los síntomas más frecuentes fueron fiebre (85%) y linfadenopatía (35%). El 54% presentaron manifestaciones atípicas, incluyendo linfohistiocitosis hemofagocítica, neumonía y neoplasia. La anemia, la trombocitopenia y la leucocitopenia fueron comunes, mientras que el 19% presentaron linfocitosis. La media de la carga viral fue de 2816 copias/ml (555-355,500). Se informaron cuatro muertes atribuidas a la infección por VEB, con valores de carga viral de 594 a 121,000 copias/ml. El 85% de los pacientes recibieron solo tratamiento sintomático, mientras que otros recibieron antivirales, esteroides y rituximab. CONCLUSIÓN: Las manifestaciones atípicas se observaron comúnmente, en especial en niños con compromiso multisistémico. El VEB debe considerarse como un potencial factor contribuyente en el diagnóstico de una amplia gama de manifestaciones clínicas.
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Infecciones por Virus de Epstein-Barr , Centros de Atención Terciaria , Humanos , México/epidemiología , Masculino , Femenino , Infecciones por Virus de Epstein-Barr/epidemiología , Infecciones por Virus de Epstein-Barr/diagnóstico , Niño , Estudios Retrospectivos , Preescolar , Adolescente , Lactante , Estudios Transversales , Carga Viral , Hospitalización/estadística & datos numéricos , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 4/genética , Fiebre/virología , Linfadenopatía/virologíaRESUMEN
We have evaluated the induction of complete (i.e., without open ends) and incomplete (i.e., with non-rejoined or open ends) chromosomal aberrations by the radiomimetic antibiotic bleomycin (BLM) in human lymphoblastoid cells immortalized with the Epstein-Barr virus (EBV). An EBV-induced lymphoblastoid cell line (T-37) was exposed to BLM (10-200 µg/mL) for 2â¯h at 37ºC, and chromosomal aberrations were analyzed 24â¯h after treatment, using PNA-FISH with pan-telomeric and pan-centromeric probes. Both complete (multicentrics, rings, compound acentric fragments, and interstitial deletions) and incomplete (incomplete chromosomes or IC, and terminal acentric fragments or TAF) chromosomal aberrations increased significantly in BLM-exposed cells, although the concentration-response relationship was non-linear. Of the acentric fragments (ace) induced by BLM, 40 % were compound fragments (CF, ace +/+). TAF (ace, +/-) and interstitial fragments (IAF, ace -/-) were induced at similar frequencies (30 %). 230 ICE were induced by BLM, of which 52 % were IC and 48 % TAF. The average ratio between total incomplete chromosome elements (ICE) and multicentrics was 1.52. These findings suggest that human lymphoblastoid cells exhibit less repair capacity than human lymphocytes, with respect to BLM-induced ICE, and that chromosomal incompleteness is a common event following exposure of these cells to BLM.
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Bleomicina , Aberraciones Cromosómicas , Herpesvirus Humano 4 , Linfocitos , Humanos , Aberraciones Cromosómicas/efectos de los fármacos , Aberraciones Cromosómicas/inducido químicamente , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/efectos de los fármacos , Bleomicina/toxicidad , Bleomicina/farmacología , Linfocitos/efectos de los fármacos , Linfocitos/virología , Línea Celular Transformada , Antibióticos Antineoplásicos/toxicidad , Antibióticos Antineoplásicos/farmacología , Transformación Celular Viral/efectos de los fármacos , Línea CelularRESUMEN
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.
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Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Herpesvirus Humano 4 , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/virología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Herpesvirus Humano 4/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Masculino , Persona de Mediana Edad , Proteínas Virales/metabolismo , Proteínas Virales/genética , Anciano , Proliferación Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Adulto , Células A549RESUMEN
INTRODUCTION: This study investigated variables associated with mortality in kidney transplant recipients (KTRs) diagnosed with post-transplant lymphoproliferative disease (PTLD) and a simultaneous Epstein-Barr virus (EBV) viremia. METHODS: This was a retrospective cohort study enrolling KTRs diagnosed with PTLD between 2018 and 2020. Outcome: death within two years after diagnosis. RESULTS: Among 1,625 KTRs who collected EBV viremia (by PCR, 2018-2020) for any reason, 238 (14.6%) had a positive viral load and 41 (17.2%) simultaneous PTLD. These 41 patients were 40.1 years old at diagnosis and 8.6 years after transplantation; 26.8% were induced with rATG and 92.7% were maintained on tacrolimus and azathioprine (TAC/AZA) as immunosuppressive regimen. Lymph nodes (75.6%) was the most common site of PTLD, followed by the gastrointestinal tract (48.8%), with 61.0% at Lugano stage IV and 80.5% monomorphic PTLD. The mean EBV viral load was 12,198 IU/mL. One- and two-year patient survival post-diagnosis was 60.4% and 46.8%, respectively. In the Cox regression analysis, age at PTLD diagnosis (HR for each year = 1.039; p < 0.001) and EBV viral load (HR for each log = 1.695; p = 0.026) were associated with risk of death. CONCLUSION: This study suggests that in patients predominantly on TAC/AZA, PTLD with simultaneous EBV positive viral load is a late event, and worse survival is associated with older age and EBV viral load at diagnosis.
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Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Trasplante de Riñón , Trastornos Linfoproliferativos , Complicaciones Posoperatorias , Carga Viral , Humanos , Trasplante de Riñón/efectos adversos , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/mortalidad , Trastornos Linfoproliferativos/virología , Trastornos Linfoproliferativos/etiología , Estudios Retrospectivos , Masculino , Femenino , Adulto , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/complicaciones , Persona de Mediana Edad , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 4/genética , Factores de Edad , Complicaciones Posoperatorias/virología , Complicaciones Posoperatorias/diagnóstico , Viremia/diagnóstico , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéuticoRESUMEN
Systemic lupus erythematosus (SLE) is a multifactorial disease characterized by the convergence of genetic, immunological, and viral elements resulting in a complex interaction of both internal and external factors. The role of the Epstein-Barr virus (EBV) and human endogenous retroviruses (HERV-E) as triggers and maintenance elements in the pathogenesis of SLE has been widely recognized. Previous studies have independently evaluated the effects of EBV and HERV-E in this disease. In this work, for the first time, these viral factors are jointly investigated in SLE patients. This study aimed at assessing the differential expression of immune regulatory genes and the incidence of specific viral pathogens (EBV and HERV-E), alongside the detailed characterization of surface markers in T- and B-lymphocytes in patients with SLE and control participants. A comparative analysis between patients with SLE and control participants was performed, evaluating the expression of phenotypic markers and genes involved in the immune response (TNF-α, IL-2, IL-6, IL-10, IFNG, TLR3), as well as HERV-E gag and EBV viral genes (LMP1 and BZLF1).A significant association between SLE and EBV was found in this study. A notable increase in EBV LMP1 gene expression was observed in patients with SLE . Also, a significant overexpression of HERV-E was observed, in addition to a considerable increase in the distribution of the cell surface marker CD27 + on T- and B-lymphocytes, observed in individuals with SLE compared to the control group. This study provides evidence regarding the role that EBV virus plays in lymphocytes in the context of SLE, highlighting how both the virus and the host gene expression may influence disease pathogenesis by altering immune regulatory pathways mediated by TNF-α, IFN-γ, and IL-10, as well as parallel overexpression of HERV-E gag. The decrease in TLR3 could indicate a compromised antiviral response, which could facilitate viral reactivation and contribute to disease activity.
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Retrovirus Endógenos , Herpesvirus Humano 4 , Leucocitos Mononucleares , Lupus Eritematoso Sistémico , Humanos , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/virología , Retrovirus Endógenos/genética , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 4/genética , Adulto , Femenino , Masculino , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/virología , Leucocitos Mononucleares/metabolismo , Perfilación de la Expresión Génica , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/genética , Persona de Mediana Edad , Linfocitos B/inmunología , Linfocitos B/virología , Estudios de Casos y Controles , Linfocitos T/inmunología , Citocinas/metabolismo , Citocinas/genéticaRESUMEN
Viral coinfection among HIV-positive patients, coupled with the development of AIDS, remains a major public health problem. The synergism between the presence of HIV and other viruses has consequences in relation to changes in the severity of the infection, as well as changes in the natural course of both infections. Several polymorphisms present in genes that encode cytokines have a relevant influence on their transcription and consequently on the production of such immunological molecules. The present study evaluated the influence of SNPs located in the promoter regions of genes encoding the cytokines INF-É£, TNF, IL-6, IL-4, and IL-2, as well as their respective plasma concentrations, in patients infected with HIV and/or EBV in the state of Pará. Additionally, this study described the epidemiological profile and compared CD4+ and CD8+ T lymphocyte counts among the groups studied. The associative analysis between the SNPs and plasma cytokine concentrations in different groups showed statistical relevance for three polymorphisms: rs2069762 (IL2), where the GG genotype demonstrated higher IL-2 levels in HIV mono-infected individuals; rs2243250 (IL4), where the CT genotype showed higher IL-4 levels in the control group; and rs2069705 (IFNG), where the TT genotype showed higher IFN-γ levels in the coinfected group. Regarding SNP associations with CD4+/CD8+ counts, significant findings were observed in HIV mono-infected individuals: the rs2069705 (IFNG) polymorphism was linked to higher CD4+ counts with the CT genotype, and rs1799964 (TNF) was associated with higher CD8+ counts with the CC genotype. Therefore, this study provides evidence that the rs2069705 (IFNG) SNP is associated with elevated IFN-γ levels, which may have pathogenic consequences, as depletion of this cytokine is concerning for people living with HIV due to its antiviral properties.
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Coinfección , Citocinas , Infecciones por Virus de Epstein-Barr , Infecciones por VIH , VIH-1 , Herpesvirus Humano 4 , Polimorfismo de Nucleótido Simple , Humanos , Infecciones por VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Infecciones por VIH/complicaciones , Brasil/epidemiología , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/complicaciones , Masculino , Adulto , Femenino , VIH-1/inmunología , VIH-1/genética , Citocinas/genética , Citocinas/sangre , Persona de Mediana Edad , Coinfección/virología , Coinfección/inmunología , Coinfección/genética , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 4/genética , Genotipo , Linfocitos T CD8-positivos/inmunología , Adulto Joven , Recuento de Linfocito CD4 , InmunogenéticaRESUMEN
Hodgkin lymphoma is histologically characterised by the presence of Hodgkin (H) and Reed-Sternberg (RS) cells originating from germinal centre B-cells rearranged in the IgV gene. The formation of multinucleated RS cells is a product of telomere organisation in a process initiated by telomere aggregate accumulation in mononuclear H cells and may be mediated by latent membrane protein 1 (LMP-1) expression. LMP-1 is the main oncoprotein of EBV and supports several tumourigenic processes. LMP-1 may rescue proapoptotic B-cells through downregulation of B-cell receptor (BCR) components, mimicking and inducing multiple distinct B-cell signalling pathways to promote proliferation and survival, such as Janus kinase-signal transducer and activator of transcription (JAK-STAT), nuclear factor-kappa b (NF-кB), and cellular MYC (c-MYC), and inducing telomere instability mainly through Telomere repeat binding factor 2 (TRF2) downregulation to promote the formation of multinucleated RS cells. This review presents recent discoveries regarding the influence of LMP-1 on the surviving cellular signalling, genomic instability and mecanical formation of HRS cells.
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Herpesvirus Humano 4 , Enfermedad de Hodgkin , Proteínas de la Matriz Viral , Enfermedad de Hodgkin/virología , Enfermedad de Hodgkin/patología , Enfermedad de Hodgkin/metabolismo , Humanos , Proteínas de la Matriz Viral/metabolismo , Proteínas de la Matriz Viral/genética , Herpesvirus Humano 4/genética , Transducción de Señal , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/metabolismo , Infecciones por Virus de Epstein-Barr/patología , Inestabilidad Genómica , Células de Reed-Sternberg/metabolismo , Células de Reed-Sternberg/patología , Células de Reed-Sternberg/virologíaRESUMEN
Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus etiologically associated with benign and malignant diseases. Since the pathogenic mechanisms of EBV are not fully understood, understanding EBV genetic diversity is an ongoing goal. Therefore, the present work describes the genetic diversity of the lytic gene BZLF1 in a sampling of 70 EBV-positive cases from southeastern Brazil. Additionally, together with the genetic regions previously characterized, the aim of the present study was to determine the impact of viral genetic factors that may influence EBV genetic diversity. Accordingly, the phylogenetic analysis of the BZLF1 indicated two main clades with high support, BZ-A and BZ-B (PP > 0.85). Thus, the BZ-A clade was the most diverse clade associated with the main polymorphisms investigated, including the haplotype Type 1 + V3 (p < 0.001). Furthermore, the multigene phylogenetic analysis (MLA) between BZLF1 and the oncogene LMP1 showed specific clusters, revealing haplotypic segregation that previous single-gene phylogenies from both genes failed to demonstrate. Surprisingly, the LMP1 Raji-related variant clusters were shown to be more diverse, associated with BZ-A/B and the Type 2/1 + V3 haplotypes. Finally, due to the high haplotypic diversity of the Raji-related variants, the number of DNA recombination-inducing motifs (DRIMs) was evaluated within the different clusters defined by the MLA. Similarly, the haplotype BZ-A + Raji was shown to harbor a greater number of DRIMs (p < 0.001). These results call attention to the high haplotype diversity of EBV in southeast Brazil and strengthen the hypothesis of the recombinant potential of South American Raji-related variants via the LMP1 oncogene.
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Infecciones por Virus de Epstein-Barr , Variación Genética , Herpesvirus Humano 4 , Filogenia , Recombinación Genética , Herpesvirus Humano 4/genética , Humanos , Brasil , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/genética , Transactivadores/genética , Masculino , Femenino , Haplotipos/genética , Adulto , Proteínas de la Matriz Viral/genética , Niño , Persona de Mediana Edad , Adolescente , Latencia del Virus/genética , Preescolar , Adulto JovenRESUMEN
BACKGROUND: This study evaluated the presence of Epstein-Barr virus type 1 (EBV-1) DNA in patients living with HIV, before and after three different topical therapy protocols for oral hairy leukoplakia (OHL). METHODS: The sample consisted of five patients treated with topical solution of 25% podophyllin resin; six with 25% podophyllin resin plus 5% acyclovir cream; and four with 25% podophyllin resin plus 1% penciclovir cream. DNA was extracted from OHL scrapings and amplified by the PCR using specific primers for EBV-1 (EBNA-1). RESULTS: Clinical healing of OHL lesions was observed across all treatment groups over time. At baseline, EBNA-1 was detected in all OHL lesions. After treatment, OHL samples from three patients treated with 25% podophyllin resin plus 5% acyclovir cream and from one patient treated with 25% podophyllin resin plus 1% penciclovir cream exhibited negative EBNA-1 viral gene encoding. Despite the clinical resolution of OHL, 11 patients (73.3%) showed EBNA-1 positivity immediately after the lesion disappeared. Three patients (20%) treated with podophyllin resin displayed both EBNA-1 positivity and a recurrence of OHL, in contrast to no recurrence in the other two groups. CONCLUSIONS: These findings suggest potential associations between treatment formulations, EBNA-1 persistence, and the recurrence of OHL lesions.
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Aciclovir , Administración Tópica , Antivirales , ADN Viral , Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Leucoplasia Vellosa , Humanos , Femenino , Masculino , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Leucoplasia Vellosa/tratamiento farmacológico , Leucoplasia Vellosa/virología , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/aislamiento & purificación , Aciclovir/uso terapéutico , Aciclovir/administración & dosificación , Persona de Mediana Edad , ADN Viral/análisis , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Infecciones por Virus de Epstein-Barr/virología , Adulto , Podofilino/uso terapéutico , Podofilino/administración & dosificación , Resultado del Tratamiento , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Reacción en Cadena de la Polimerasa , Guanina/análogos & derivados , Guanina/uso terapéutico , Guanina/administración & dosificaciónRESUMEN
OBJECTIVE: Monitoring the disease status of Epstein-Barr virus (EBV)-related hemophagocytic lymphohistiocytosis (HLH) patients is crucial. This study aimed to investigate the different strategies and outcomes of patients with EBV-HLH and re-elevated EBV-DNA. METHOD: A retrospective analysis was conducted on 20 patients diagnosed with EBV-HLH. Clinical features, laboratory tests, treatments, plasma EBV-DNA levels, and outcomes were assessed. Three cases were highlighted for detailed analysis. RESULTS: Nine of the 20 patients had a re-elevation of EBV-DNA during treatment, and 55.5 % (5/9) experienced relapses. Patients with persistently positive plasma EBV-DNA (n = 4) and those with re-elevated EBV-DNA after conversion (n = 9) showed a significantly higher relapse rate compared to those with persistently negative EBV-HLH (n = 7) (p < 0.05). Among the highlighted cases, Case 1 exhibited plasma EBV-DNA re-elevation after four weeks of treatment without relapse, maintaining stability with the original treatment regimen, and eventually, his plasma EBV-DNA turned negative. In Case 2, plasma EBV-DNA was elevated again with a recurrence of HLH after L-DEP. Consequently, she underwent allogeneic hematopoietic stem cell transplantation and eventually achieved complete remission (CR) with negative plasma EBV-DNA. Case 3 experienced plasma EBV-DNA re-elevation after L-DEP but remained in CR, discontinuing chemotherapy without relapse. CONCLUSION: The re-elevation of plasma EBV-DNA during EBV-HLH treatment poses challenges in determining disease status and treatment strategies. Optimal management decisions require a combination of the level of elevated EBV-DNA, the intensity of hyperinflammation, and the patient's immune function.
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ADN Viral , Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Linfohistiocitosis Hemofagocítica , Recurrencia , Humanos , Linfohistiocitosis Hemofagocítica/terapia , Linfohistiocitosis Hemofagocítica/sangre , Linfohistiocitosis Hemofagocítica/virología , Estudios Retrospectivos , Masculino , Infecciones por Virus de Epstein-Barr/sangre , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/terapia , Femenino , ADN Viral/sangre , Preescolar , Niño , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/aislamiento & purificación , Lactante , Adolescente , Resultado del Tratamiento , Relevancia ClínicaRESUMEN
INTRODUCTION: Gastric epithelial tumors exhibit morphological heterogeneity, diverse biological behaviors, and different oncopathological pathways. The Cancer Genome Atlas (TCGA) proposed a molecular classification of gastric adenocarcinomas based on genetic and molecular findings, which shows particular characteristics of diagnosis, prognosis, and indirectly, therapeutic alternatives. Within this classification, Epstein-Barr virus-positive (EBV+) and high microsatellite instability (MSI-H) subtypes stand out as subtypes that present a less aggressive biological behavior and a highly mutilated phenotype. This study conducted a systematic review with an emphasis on epidemiological and prognostic factors based on the molecular classification proposed by TCGA. METHODS: A broad, comprehensive, and reproducible search with methodological rigor was conducted for study selection using the ROBINS-I and GRADEpro protocols and appropriate combinations of keywords. RESULTS: A total of 25 studies were selected: six with a complete classification similar to TCGA and 19 with a distinction between MSI-H and EBV+. The application of meta-analysis calculations reinforces the prevalence of positive Epstein-Barr adenocarcinomas in males and high microsatellite instability in females, with a high level of certainty of evidence and low risk of bias in the analyzed studies due to the rigorous methods used. CONCLUSION: The molecular classification proposed by TCGA shows limited dissemination, with MSI-H and EBV+ subtypes being the most researched, probably due to the benefit of the association with immunotherapies. However, the subclassification cannot be restricted to less than a quarter of the cases, and improvements in this aspect are urgent for the construction of knowledge on this important topic of global health.
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Adenocarcinoma , Infecciones por Virus de Epstein-Barr , Neoplasias Gástricas , Masculino , Femenino , Humanos , Herpesvirus Humano 4/genética , Infecciones por Virus de Epstein-Barr/epidemiología , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Inestabilidad de Microsatélites , Repeticiones de Microsatélite , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Adenocarcinoma/epidemiología , Adenocarcinoma/genética , Adenocarcinoma/patologíaRESUMEN
OBJECTIVES: Nasopharyngeal Carcinoma (NPC) is a common malignant tumor of nasopharyngeal mucosal epithelium in clinical practice. Radiotherapy and chemotherapy are the main treatment methods at present, but the therapeutic effect is still unsatisfactory. Studies have shown that exosomes and microRNAs (miRNAs) play an important role in the development of cancer. Therefore, this study aimed to investigate the effects of NPC derived exosomes on NPC and their molecular mechanisms. METHODS: Serum was collected from healthy subjects, Epstein-Barr Virus (EBV) infected patients and NPC patients (nâ¯=â¯9 group) and exosomes were extracted separately. High-throughput sequencing of exosomes was performed to screen differentially expressed miRNAs. The function of the screened miRNA was identified by treating NPC cells with exosomes. The target gene of miRNA was identified using the dual-luciferase assay. Real-Time quantitative Polymerase Chain Reaction (RT-qPCR) was used to determine the levels of miR-99a-5p and Bromodomain Adjacent Tozinc finger domain protein 2A (BAZ2A). Cell Counting Kit-8 assay, flow cytometry, and wound healing assay were utilized to detect cell viability, cell cycle and apoptosis, and migration ability. The protein levels were evaluated by Western blot. RESULTS: MiR-99a-5p was identified as the most significant differentially expressed miRNA in exosomes (pâ¯<â¯0.05). The proliferation and migration of NPC cells were extremely facilitated by exosomes, accompanied by the suppressed apoptosis, upregulated BAZ2A, Monocyte Chemotactic Protein-1 (MCP1), and Vascular Endothelial Growth Factor A (VEGFA), and downregulation of Interleukin (IL)-1ß and Nuclear Transcription Factor-κB (NF-κB) (pâ¯<â¯0.05). BAZ2A was a target gene of miR-99a-5p. Furthermore, the regulatory effect of exosomes on the proliferation, migration, and apoptosis was significantly abolished by overexpression of miR-99a-5p or downregulation of BAZ2A (pâ¯<â¯0.05). CONCLUSION: NPC derived exosomes facilitated the proliferation and migration of NPC through regulating the miR-99a-5p/BAZ2A axis.
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Infecciones por Virus de Epstein-Barr , Exosomas , MicroARNs , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patología , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Exosomas/genética , Exosomas/metabolismo , Exosomas/patología , Infecciones por Virus de Epstein-Barr/genética , Línea Celular Tumoral , Proliferación Celular , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Regulación Neoplásica de la Expresión Génica , Proteínas que Contienen Bromodominio , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismoRESUMEN
BACKGROUND: Epstein-Barr virus (EBV) is a human gammaherpesvirus etiologically linked to several benign and malignant diseases. EBV-associated malignancies exhibit an unusual global distribution that might be partly attributed to virus and host genetic backgrounds. OBJECTIVES: To assemble a new genome of EBV (CEMO3) from a paediatric Burkitt's lymphoma from Rio de Janeiro State (Southeast Brazil). In addition, to perform global phylogenetic analysis using complete EBV genomes, including CEMO3, and investigate the genetic relationship of some South American (SA) genomes through EBV subgenomic targets. METHODS: CEMO3 was sequenced through next generation sequencing and its coverage and gaps were corrected through the Sanger method. CEMO3 and 67 EBV genomes representing diverse geographic regions were evaluated through maximum likelihood phylogenetic analysis. Further, the polymorphism of subgenomic regions of some SA EBV genomes were assessed. FINDINGS: The whole bulk tumour sequencing yielded 23,217 reads related to EBV, which 172,713 base pairs of the newly EBV genome CEMO3 was assembled. The CEMO3 and most SA EBV genomes clustered within the SA subclade closely related to the African Raji strain, forming the South American/Raji clade. Notably, these Raji-related genomes exhibit significant genetic diversity, characterised by distinctive synapomorphies at some gene levels absent in the original Raji strain. CONCLUSION: The CEMO3 represents a new South American EBV genome assembled. Albeit the majority of EBV genomes from SA are Raji-related, it harbours a high diversity different from the original Raji strain.
Asunto(s)
Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Niño , Humanos , Herpesvirus Humano 4/genética , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/patología , Filogenia , Genoma Viral/genética , BrasilRESUMEN
Aberrant skipping of coding exons in CD19 and CD22 compromises the response to immunotherapy in B-cell malignancies. Here, we showed that the MS4A1 gene encoding human CD20 also produces several messenger RNA (mRNA) isoforms with distinct 5' untranslated regions. Four variants (V1-4) were detected using RNA sequencing (RNA-seq) at distinct stages of normal B-cell differentiation and B-lymphoid malignancies, with V1 and V3 being the most abundant. During B-cell activation and Epstein-Barr virus infection, redirection of splicing from V1 to V3 coincided with increased CD20 positivity. Similarly, in diffuse large B-cell lymphoma, only V3, but not V1, correlated with CD20 protein levels, suggesting that V1 might be translation-deficient. Indeed, the longer V1 isoform contained upstream open reading frames and a stem-loop structure, which cooperatively inhibited polysome recruitment. By modulating CD20 isoforms with splice-switching morpholino oligomers, we enhanced CD20 expression and anti-CD20 antibody rituximab-mediated cytotoxicity in a panel of B-cell lines. Furthermore, reconstitution of CD20-knockout cells with V3 mRNA led to the recovery of CD20 positivity, whereas V1-reconstituted cells had undetectable levels of CD20 protein. Surprisingly, in vitro CD20-directed chimeric antigen receptor T cells were able to kill both V3- and V1-expressing cells, but the bispecific T-cell engager mosunetuzumab was only effective against V3-expressing cells. To determine whether CD20 splicing is involved in immunotherapy resistance, we performed RNA-seq on 4 postmosunetuzumab follicular lymphoma relapses and discovered that in 2 of them, the downregulation of CD20 was accompanied by a V3-to-V1 shift. Thus, splicing-mediated mechanisms of epitope loss extend to CD20-directed immunotherapies.
Asunto(s)
Infecciones por Virus de Epstein-Barr , Neoplasias , Humanos , Empalme Alternativo , ARN Mensajero/genética , Regiones no Traducidas 5' , Infecciones por Virus de Epstein-Barr/genética , Herpesvirus Humano 4/genética , Antígenos CD20/genética , Isoformas de Proteínas/genética , Inmunoterapia , Biosíntesis de Proteínas , Neoplasias/genéticaRESUMEN
EpsteinBarr virus (EBV) is an oncovirus associated with various neoplasms, including breast cancer (BC). EBVassociated oncogenesis requires the action of several viral molecules, such as EBV nuclear antigen 3C, latent membrane protein 1, microRNAs and long noncoding RNAs, which are able of manipulating the cellular machinery, inducing an evasion of the immune system, blocking apoptosis processes, promoting cell survival and metastasis. The risk of developing cancer is associated with epigenetic alterations and alterations in various signaling pathways. The activation of all these molecules can modify the expression of EBV proteins with oncogenic activity, influencing the oncogenic process. It is clear that BC, being multifactorial, presents a greater complexity; in numerous cases, the infection associated with EBV may be crucial for this neoplasia, if particular conditions for both the virus and host are present. In the present review, all these variables are analyzed in an aim to improve the understanding of the participation of EBV in BC.
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Neoplasias de la Mama , Infecciones por Virus de Epstein-Barr , Humanos , Femenino , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Neoplasias de la Mama/genética , Microambiente Tumoral/genética , Transformación Celular Neoplásica , Carcinogénesis/genéticaRESUMEN
The Epstein-Barr virus (EBV) has been associated with gastric cancer (GC), one of the deadliest malignancies in Chile and the world. Little is known about Chilean EBV strains. This study aims to investigate the frequency and genetic diversity of EBV in GC in patients in southern Chile. To evaluate the prevalence of EBV in GC patients from the Chilean population, we studied 54 GC samples using the gold standard detection method of EBV-encoded small RNA (EBER). The EBV-positive samples were subjected to amplification and sequencing of the Epstein-Barr virus nuclear protein 3A (EBNA3A) gene to evaluate the genetic diversity of EBV strains circulating in southern Chile. In total, 22.2% of the GC samples were EBV-positive and significantly associated with diffuse-type histology (p = 0.003). Phylogenetic analyses identified EBV-1 and EBV-2 in the GC samples, showing genetic diversity among Chilean isolates. This work provides important information for an epidemiological follow-up of the different EBV subtypes that may cause GC in southern Chile.
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Infecciones por Virus de Epstein-Barr , Neoplasias Gástricas , Humanos , Herpesvirus Humano 4/genética , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/epidemiología , Chile/epidemiología , Filogenia , Variación GenéticaRESUMEN
RNA interference (RNAi) treatment has been proven to be an important therapeutic approach in cancer based on downregulation of target-oncogenes, but its clinical efficacy still needs further investigation. LMP1 is usually presented by Epstein-Barr virus (EBV)-positive tumor cells like EBV-associated nasopharyngeal carcinoma (NPC) and acts as an oncogene in tumorigenesis. However, the mechanism of LMP1 as a proto-oncogene in nasopharyngeal carcinoma is still unclear. Two sequence-specific shRNAs 1 and 2 were designed to target the different nucleotide loci of EBV latent antigen LMP1 gene and a series of in vivo and in vitro experiments were performed to investigate the therapeutic effect of sequence-specific shRNAs targeting LMP1 and its related molecular mechanisms in EBV-positive NPC. LMP1-shRNA2 generated a truncated LMP1 mRNA and protein, whereas LMP1-shRNA1 completely blocked LMP1 mRNA and protein expression. Both LMP1-shRNAs inhibited the proliferation and migration of NPC cells overexpressing LMP1 (NPC-LMP1) as well as the NPC-associated myeloid-derived suppressor cell (MDSC) expansion in vitro. However, LMP1-shRNA2 maintained the immunogenicity of NPC-LMP1 cells, which provoked MHC-class I-dependent T cell recognition. LMP1-shRNAs inhibited tumor growth in nude mice but did not reach statistical significance compared to control groups, while the LDH nanoparticle loaded LMP1-shRNAs and the antigen-specific T cells induced by NPC-LMP1 cells treated with LMP1-shRNA2 significantly reduced tumor growth in vivo. LMP1-RNAi-based anti-tumor therapy could be a new hope for the clinical efficacy of RNAi treatment of tumors like NPC.
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Carcinoma , Infecciones por Virus de Epstein-Barr , Neoplasias Nasofaríngeas , Animales , Ratones , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/terapia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Carcinoma/metabolismo , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/metabolismo , Interferencia de ARN , Ratones Desnudos , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , ARN Mensajero/metabolismo , Línea Celular TumoralRESUMEN
In 2017, the World Health Organization (WHO) confirmed a new entity, Epstein Barr virus (EBV) + Diffuse large B cell lymphoma (DLBCL), not otherwise specified (NOS). Traces of EBV transcripts were described in lymphomas, including DLBCL, that were diagnosed as EBV negative by conventional methods. The aim of this study was to detect viral genome by qPCR, as well as LMP1 and EBNA2 transcripts, with a more sensitive method in DLBCL cases from Argentina. Fourteen cases originally considered as EBV negative expressed LMP1 and/or EBNA2 transcripts. In addition, LMP1 and/or EBNA2 transcripts were also observed in bystander cells. However, EBERs+ cells cases by conventional ISH showed higher numbers of cells with LMP1 transcripts and LMP1 protein. In the cases that were EBERS- in tumor cells but with expression of LMP1 and/or EBNA2 transcripts, the viral load was below the limit of detection. This study provides further evidence that EBV could be detected in tumor cells by more sensitive methods. However, higher expression of the most important oncogenic protein, LMP1, as well as increased viral load, are only observed in cases with EBERs+ cells by conventional ISH, suggesting that traces of EBV might not display a key role in DLBCL pathogenesis.
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Infecciones por Virus de Epstein-Barr , Linfoma de Células B Grandes Difuso , Humanos , Adulto , Niño , Herpesvirus Humano 4/genética , Linfoma de Células B Grandes Difuso/patología , Argentina , Antígenos Nucleares del Virus de Epstein-Barr/genética , Proteínas de la Matriz Viral/genéticaRESUMEN
Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease of the central nervous system (CNS). The etiology of MS is not well understood, but it's likely one of the genetic and environmental factors. Approximately 85% of patients have relapsing-remitting MS (RRMS), while 10-15% have primary progressive MS (PPMS). Epstein-Barr virus (EBV) and Human herpesvirus 6 (HHV-6), members of the human Herpesviridae family, are strong candidates for representing the macroenvironmental factors associated with MS) pathogenesis. Antigenic mimicry of EBV involving B-cells has been implicate in MS risk factors and concomitance of EBV and HHV-6 latent infection has been associated to inflammatory MS cascade. To verify the possible role of EBV and HHV-6 as triggering or aggravating factors in RRMS and PPMS, we compare their frequency in blood samples collected from 166 MS patients. The presence of herpes DNA was searched by real-time PCR (qPCR). The frequency of EBV and HHV-6 in MS patients were 1.8% (3/166) and 8.9% (14/166), respectively. Among the positive patients, 100% (3/3) EBV and 85.8% (12/14) HHV-6 are RRMS and 14.4% (2/14) HHV-6 are PPMS. Detection of EBV was 1.2% (2/166) and HHV-6 was 0.6% (1/166) in blood donors. About clinical phenotype of these patients, incomplete multifocal myelitis, and optic neuritis were the main CNS manifestations. These are the first data about concomitant infection of these viruses in MS patients from Brazil. Up to date, our findings confirm a higher prevalence in female with MS and a high frequency of EBV and HHV-6 in RRMS patients.
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Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 6 , Esclerosis Múltiple , Enfermedades Neurodegenerativas , Humanos , Femenino , Herpesvirus Humano 4/genética , Herpesvirus Humano 6/genética , ADN Viral , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/epidemiología , Brasil/epidemiologíaRESUMEN
OPINION STATEMENT: Nasopharyngeal carcinoma (NPC) is a rare malignancy, endemic in China, that is commonly diagnosed in locally advanced scenarios. Its pathogenesis is strongly associated with Epstein-Barr virus (EBV), an infection for which measuring EBV plasma DNA levels has helped as a prognostic factor guiding treatment options, including a stronger treatment in those with high titers. Additionally, tobacco and alcohol are often implicated in EBV-negative patients. The local disease is treated with radiotherapy alone, preferentially intensity modulated radiotherapy. For locally advanced disease, the backbone treatment is concurrent chemoradiotherapy with the ongoing research dilemma being adding adjuvant chemotherapy or induction chemotherapy. The ongoing research is focused not only on identifying patients that will benefit from adjuvant or induction chemotherapy, but also on identifying the best chemotherapeutic regimen, regimen alternatives to diminish toxicity, the role that immune checkpoint inhibitors play, and the use of molecularly guided treatment targeting patients with NPC whether driven by EBV or tobacco and alcohol. Knowing the precise oncogenesis of NPC not only offers a better understanding of the role that EBV plays in this tumor but also helps create targeted therapies that could potentially block important pathways such as the NF-κB pathway. Much is yet to be done, but the prognosis and management of NPC patients have changed drastically, offering precise treatment methods and excellent control of the disease, even in locally advanced scenarios.