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1.
Medicine (Baltimore) ; 100(8): e24555, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33663063

RESUMO

ABSTRACT: Some nasopharyngeal carcinoma (NPC) patients may present convincing radiological evidence mimicking residual or recurrent tumor after radiotherapy. However, by means of biopsies and long term follow-up, the radiologically diagnosed residuals/recurrences are not always what they appear to be. We report our experience on this "phantom tumor" phenomenon. This may help to avoid the unnecessary and devastating re-irradiation subsequent to the incorrect diagnosis.In this longitudinal cohort study, we collected 19 patients of image-based diagnosis of residual/recurrent NPC during the period from Feb, 2010 to Nov. 2016, and then observed them until June, 2019. They were subsequently confirmed to have no residual/recurrent lesions by histological or clinical measures. Image findings and pathological features were analyzed.Six patients showed residual tumors after completion of radiotherapy and 13 were radiologically diagnosed to have recurrences based on magnetic resonance imaging (MRI) criteria 6 to 206 months after radiotherapy. There were 3 types of image patterns: extensive recurrent skull base lesions (10/19); a persistent or residual primary lesion (3/19); lesions both in the nasopharynx and skull base (6/19). Fourteen patients had biopsy of the lesions. The histological diagnoses included necrosis/ inflammation in 10 (52.7%), granulation tissue with inflammation in 2, and reactive epithelial cell in 1. Five patients had no pathological proof and were judged to have no real recurrence/residual tumor based on the absence of detectable plasma EB virus DNA and subjective judgment. These 5 patients have remained well after an interval of 38-121 months without anti-cancer treatments.Image-based diagnosis of residual or recurrent nasopharyngeal carcinoma may be unreliable. False positivity, the "phantom tumor phenomenon", is not uncommon in post-radiotherapy MRI. This is particularly true if the images show extensive skull base involvement at 5 years or more after completion of radiotherapy. MRI findings compatible with NPC features must be treated as a real threat until proved otherwise. However, the balance between under- and over-diagnosis must be carefully sought. Without a pathological confirmation, the diagnosis of residual or recurrent NPC must be made taking into account physical examination results, endoscopic findings and Epstein-Barr virus viral load. A subjective medical judgment is needed based on clinical and laboratory data and the unique anatomic complexities of the nasopharynx.


Assuntos
Carcinoma Nasofaríngeo/diagnóstico por imagem , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/diagnóstico por imagem , Neoplasias Nasofaríngeas/radioterapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Herpesvirus Humano 4/genética , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/terapia , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/patologia , Neoplasia Residual/patologia , Carga Viral
2.
An Bras Dermatol ; 96(2): 184-187, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33627249

RESUMO

Epstein Barr virus-associated smooth muscle tumors are an uncommon neoplasm that occurs in immunosuppressed patients of any age. Usually, it presents as multifocal tumors mainly in the spinal cord, epidural region, gastrointestinal tract and liver, upper respiratory tract and skin, the latest with few cases reported in the literature and related with human immunodeficiency virus infection and acquired immune deficiency syndrome. The authors present the first case of a Colombian adult patient with human immunodeficiency virus infection and multifocal Epstein Barr virus-associated smooth muscle tumors in the skin and epidural region, confirmed by histopathology, immunohistochemistry and in situ hybridization studies.


Assuntos
Infecções por Vírus Epstein-Barr , Infecções por HIV , Tumor de Músculo Liso , Adulto , Infecções por Vírus Epstein-Barr/complicações , Infecções por HIV/complicações , Herpesvirus Humano 4/genética , Humanos , RNA Viral
3.
Arkh Patol ; 83(1): 18-24, 2021.
Artigo em Russo | MEDLINE | ID: mdl-33512123

RESUMO

THE AIM OF THE STUDY: Is to establish the relationship between the persistence of viral antigens of the Epstein-Barr virus (EBV) and the cellular composition of the immune microenvironment of tumor tissue and the mucous membrane of peritumoral area in gastric cancer. MATERIAL AND METHODS: We used samples of surgical material from 55 patients with a verified diagnosis of gastric cancer. The expression of CD4, CD8, CD68, CD1a and LMP-1 was assessed. The results were assessed by the morphometric method. We selected three fields of view (magnification x200) in tumor tissue and in peritumoral areas separately and counted an absolute number of cells with positive staining with further calculation of the average number of cells and the median. RESULTS: LMP-1-negative tumors with LMP-1 expression in epithelium of peritumoral area were characterized by the highest density of CD4+ lymphocyte infiltration in the central part of the tumor; the highest density of CD8+ lymphocyte infiltration in the mucous membrane of peritumoral area (p=0.0190); the highest density of infiltration by macrophages in the mucous membrane of peritumoral area (p=0.2492); the highest density of infiltration by CD1a+ cells in the mucous membrane of peritumoral area (p=0.1503). The highest density of infiltration with CD1a+ cells was characteristic for LMP-1-positive and LMP-1-negative tumors (p=0.0813). The persistence of the LMP-1 viral antigen in the glandular epithelium of the peritumoral area in our sample does not have a statistically significant effect on the prognosis of the disease (RR=1.7718; p=0.0885) but there is a tendency towards a negative predictive value. CONCLUSION: High density of infiltration of glandular epithelium of peritumoral area with the expression of LMP-1 by CD4+ and CD8+ lymphocytes is most likely associated with the activation of the cellular immune response and may be one of the signs of the persistence of viral antigens. It was shown for the first time that the phenomenon of persistence of the LMP-1 viral antigen is characterized by a trend towards negative predictive value for patients with gastric cancer.


Assuntos
Herpesvirus Humano 4 , Neoplasias Gástricas , Antígenos Virais , Antígenos Nucleares do Vírus Epstein-Barr , Herpesvirus Humano 4/genética , Humanos , Microambiente Tumoral , Proteínas da Matriz Viral
4.
BMC Infect Dis ; 21(1): 17, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407199

RESUMO

BACKGROUND: Hydroa Vacciniforme-like Lymphoproliferative Disorder (HV-LPD) is the name given to a group of Epstein-Barr virus (EBV)-associated diseases. It resembles hydroa vacciniforme (HV), the rarest form of photosensitivity, and is a T-cell disorder associated with an Epstein-Barr virus infection. The majority of diagnosed cases occur in East Asia and South America. It is rare in the United States and Europe. Multiple studies have revealed the clinical manifestation of an enlarged liver, but no gold standard such as pathology has yet supported this as a clinical sign of HV-LPD. CASE PRESENTATION: Here, we report a case of a 34-year-old Asian female with definite liver invasion. The patient had complained of a recurring facial rash for many years. The patient was admitted to the hospital because of an enlarged liver. After hospitalization, she was given an EB virus nucleic acid test. The EB virus nucleic acid test was positive, and pathological examination suggested that HV-LPD had invaded the skin, bone marrow, and liver. After being given antiviral treatment, the patient's symptoms were mitigated. CONCLUSIONS: Our case confirms the liver damage was caused by HV-LPD and the effectiveness of antiviral treatment.


Assuntos
Medula Óssea/patologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Herpesvirus Humano 4/genética , Hidroa Vaciniforme/complicações , Hidroa Vaciniforme/diagnóstico , Fígado/patologia , Transtornos Linfoproliferativos/complicações , Transtornos Linfoproliferativos/diagnóstico , Adulto , Antivirais/uso terapêutico , Pequim , Medula Óssea/virologia , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/virologia , Exantema/complicações , Exantema/tratamento farmacológico , Feminino , Hepatomegalia/tratamento farmacológico , Hepatomegalia/virologia , Humanos , Hidroa Vaciniforme/tratamento farmacológico , Hidroa Vaciniforme/patologia , Fígado/virologia , Linfoma de Células T/complicações , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/virologia , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/patologia , Pele/patologia , Resultado do Tratamento
5.
J Cancer Res Clin Oncol ; 147(3): 713-723, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33392659

RESUMO

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a rare epithelial carcinoma arising from the nasopharyngeal region. The pathogenesis of NPC is linked to Epstein-Barr virus (EBV) infection, although genetics and lifestyle factors appears to be also implicated. NKG2D is an immunoreceptor expressed by NK and T-cell subsets that recognizes MICA protein and other ligands on tumor cells. NKG2D interaction with MICA plays a role in the immunosurveillance to viruses and cancer. METHODS: We investigated potential associations between functional polymorphisms in NKG2D and MICA genes with NPC susceptibility. We conducted a case-control study including 255 Vietnamese patients with EBV + non-differentiated NPC and 220 healthy controls. RESULTS: We observed a significant association between the LNK/LNK genotype of rs1049174 (a variant associated with lower NKG2D receptor expression and reduced NK cell cytotoxicity) and increased susceptibility to NPC (adjusted OR = 1.66, 95% CI 1.07-2.59; p = 0.024). Similarly, the AA genotype of MICA rs2596542 was significantly associated with NPC (adjusted OR = 2.12; 95% CI 1.22-3.81; p = 0.009). In addition, tumor specimens of NPC patients with the AA genotype displayed a higher expression level of MICA proteins and showed higher EBV titers compared with tumor tissues from patients with the GG or GA genotypes. Higher EBV copy numbers were also observed in tumors with the A allele of MICA rs1051792 (also known as MICA-129 Met/Val) compared with those with the G allele; however, MICA rs1051792 variants were not associated with NPC susceptibility. These results suggest that genetic variants in components of the NKG2D axis may influence the individual susceptibility to EBV-induced NPC.


Assuntos
Infecções por Vírus Epstein-Barr/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/virologia , Adulto , Estudos de Casos e Controles , DNA Viral/análise , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/patologia , Feminino , Predisposição Genética para Doença , Variação Genética , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Antígenos de Histocompatibilidade Classe I/biossíntese , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imuno-Histoquímica , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/patologia , Polimorfismo de Nucleotídeo Único
6.
Recent Results Cancer Res ; 217: 197-207, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33200367

RESUMO

Epstein-Barr virus (EBV) is associated with a variety of malignancies including post-transplant lymphoproliferative disease (PTLD). These include B and T cell lymphomas, epithelial, and mesenchymal tumors. The virus is ubiquitous, transmitted in saliva, and not usually associated with the development of malignancy. PTLD is usually associated with EBV when it occurs soon after the transplant. Measurement of viral DNA in blood, especially plasma, may be useful in the diagnosis of PTLD. Treatment approaches include withdrawal of immunosuppression, monoclonal antibodies or antibody conjugates, cytotoxic chemotherapy, and a variety of virus-specific treatments such as adoptive cellular therapy with EBV-specific T cells. Approaches to prevention include selection of immunosuppressive regimens that minimize the risk. In the future, EBV vaccines may be available for potential transplant recipients.


Assuntos
Infecções por Vírus Epstein-Barr , Transtornos Linfoproliferativos , DNA Viral , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/genética , Humanos , Transtornos Linfoproliferativos/virologia
7.
BMJ Case Rep ; 13(12)2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33370940

RESUMO

A 17-year-old Caucasian male presented to ENT with angular stomatitis, oral ulceration and cervical lymphadenopathy. Over the subsequent 18 months he developed recurrent upper respiratory tract infections, pyrexia of unknown origin, oral ulceration and maxillary sinus osteomyelitis. Extensive investigation ensued from various specialties. Positive investigations included a mild but persistently elevated serum Epstein-Barr virus PCR; however, no unifying diagnosis was elicited. It is noteworthy that a significant factor contributing to a delay in his diagnosis was poor compliance with invasive investigations. Ultimately, deteriorating liver function prompted liver biopsy which confirmed a diagnosis of chronic active Epstein-Barr virus infection (CAEBV). This enabled referral for curative treatment in the form of a stem cell transplant. CAEBV is extremely rare in Western countries. Due to fatal complications early diagnosis is critical for successful treatment. Our case highlights the need for regular clinical re-evaluation and a comprehensive multispecialty approach in such cases.


Assuntos
Infecções por Vírus Epstein-Barr/diagnóstico , Herpesvirus Humano 4/isolamento & purificação , Fígado/patologia , Equipe de Assistência ao Paciente , Adolescente , Biópsia , Doença Crônica/terapia , DNA Viral/sangue , DNA Viral/isolamento & purificação , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/terapia , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/genética , Humanos , Fígado/virologia , Testes de Função Hepática , Masculino , Encaminhamento e Consulta , Transplante de Células-Tronco
8.
Int J Mol Sci ; 21(24)2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33321820

RESUMO

Gastric cancer (GC) is a deadly disease with poor prognosis that is characterized by heterogeneity. New classifications based on histologic features, genotypes, and molecular phenotypes, for example, the Cancer Genome Atlas subtypes and those by the Asian Cancer Research Group, help understand the carcinogenic differences in GC and have led to the identification of an Epstein-Barr virus (EBV)-related GC subtype (EBVaGC), providing new indications for tailored treatment and prognostic factors. This article provides a review of the features of EBVaGC and an update on the latest insights from EBV-related research with a particular focus on the strict interaction between EBV infection and the gastric tumor environment, including the host immune response. This information may help increase our knowledge of EBVaGC pathogenesis and the mechanisms that sustain the immune response of patients since this mechanism has been demonstrated to offer a survival advantage in a proportion of patients with GC.


Assuntos
Herpesvirus Humano 4/genética , Neoplasias Gástricas/metabolismo , Animais , Transformação Celular Viral , Herpesvirus Humano 4/patogenicidade , Interações Hospedeiro-Patógeno , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/virologia
9.
PLoS Pathog ; 16(12): e1009023, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33382850

RESUMO

Extracellular vesicles (EV) mediate intercellular communication events and alterations in normal vesicle content contribute to function and disease initiation or progression. The ability to package a variety of cargo and transmit molecular information between cells renders EVs important mediators of cell-to-cell crosstalk. Latent membrane protein 1 (LMP1) is a chief viral oncoprotein expressed in most Epstein-Barr virus (EBV)-associated cancers and is released from cells at high levels in EVs. LMP1 containing EVs have been demonstrated to promote cell growth, migration, differentiation, and regulate immune cell function. Despite these significant changes in recipient cells induced by LMP1 modified EVs, the mechanism how this viral oncogene modulates the recipient cells towards these phenotypes is not well understood. We hypothesize that LMP1 alters EV content and following uptake of the LMP1-modified EVs by the recipient cells results in the activation of cell signaling pathways and increased gene expression which modulates the biological properties of recipient cell towards a new phenotype. Our results show that LMP1 expression alters the EV protein and microRNA content packaged into EVs. The LMP1-modified EVs also enhance recipient cell adhesion, proliferation, migration, invasion concomitant with the activation of ERK, AKT, and NF-κB signaling pathways. The LMP1 containing EVs induced transcriptome reprogramming in the recipient cells by altering gene expression of different targets including cadherins, matrix metalloproteinases 9 (MMP9), MMP2 and integrin-α5 which contribute to extracellular matrix (ECM) remodeling. Altogether, our data demonstrate the mechanism in which LMP1-modified EVs reshape the tumor microenvironment by increasing gene expression of ECM interaction proteins.


Assuntos
Infecções por Vírus Epstein-Barr/metabolismo , Vesículas Extracelulares/metabolismo , Proteínas da Matriz Viral/metabolismo , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Infecções por Vírus Epstein-Barr/fisiopatologia , Vesículas Extracelulares/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Herpesvirus Humano 4/patogenicidade , Humanos , MicroRNAs/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/virologia , Invasividade Neoplásica/genética , Transdução de Sinais , Microambiente Tumoral , Proteínas da Matriz Viral/fisiologia
10.
Nat Commun ; 11(1): 5405, 2020 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-33106493

RESUMO

Epstein-Barr virus (EBV) is a γ-herpesvirus associated with the occurrence of several human malignancies. BBRF2 and BSRF1 are two EBV tegument proteins that have been suggested to form a hetero-complex and mediate viral envelopment, but the molecular basis of their interaction and the functional mechanism of this complex remains unknown. Here, we present crystal structures of BBRF2 alone and in complex with BSRF1. BBRF2 has a compact globular architecture featuring a central ß-sheet that is surrounded by 10 helices, it represents a novel fold distinct from other known protein structures. The central portion of BSRF1 folds into two tightly associated antiparallel α-helices, forming a composite four-helix bundle with two α-helices from BBRF2 via a massive hydrophobic network. In vitro, a BSRF1-derived peptide binds to BBRF2 and reduces the number of viral genome copies in EBV-positive cells. Exogenous BBRF2 and BSRF1 co-localize at the Golgi apparatus. Furthermore, BBRF2 binds capsid and capsid-associated proteins, whereas BSRF1 associates with glycoproteins. These findings indicate that the BBRF2-BSRF1 complex tethers EBV nucleocapsids to the glycoprotein-enriched Golgi membrane, facilitating secondary envelopment.


Assuntos
Herpesvirus Humano 4/metabolismo , Capsídeo/química , Capsídeo/metabolismo , Infecções por Vírus Epstein-Barr/virologia , Genoma Viral , Herpesvirus Humano 4/química , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/crescimento & desenvolvimento , Humanos , Ligação Proteica , Conformação Proteica em alfa-Hélice
11.
Zhonghua Bing Li Xue Za Zhi ; 49(10): 1009-1014, 2020 Oct 08.
Artigo em Chinês | MEDLINE | ID: mdl-32992414

RESUMO

Objective: To investigate the clinicopathological features of primary Epstein-Barrvirus (EBV) positive nodal T/NK-cell lymphomas (EBV+nodal TNKL). Methods: The clinicopathological features of 7 cases of EBV+nodal TNKL diagnosed between November 2015 and May 2019 at the First Affiliated Hospital of Zhengzhou University were analyzed using immunohistochemistry, PCR gene rearrangement and in situ hybridization.Follow-up data were also collected. Results: There were 5 males and 2 females with a median age of 54 years (ranged from 41 to 75 years). All patients presented with multiple lymphadenopathies and common B symptoms (5/7) and at an advanced Ann Arbor stage Ⅲ/Ⅳ(6/7). Bone marrow involvementwas detected in 1 patient.Six cases of T-cell origin had monomorphic patterns, and the tumor cells showed CD56 negativity and TCRαß+/TCRγδ- with T-cell clonality. One case of NK-cell origin had polymorphic pattern, and the tumor cells showed CD56 positivity and TCRαß-/TCRγδ-without T-cell clonality. All cases were positive for the cytotoxic markers, but showed various CD4/CD8 expression. All 7 cases were diffusely positive for EBV (>100 cell/high power field). Six of the patients received chemotherapy, and 1 patient declined the treatments. During the follow-up period ranging from 3 to 48 months, 5 of the 7 patients died of the disease. Conclusions: EBV+nodal TNKL is a rare entity and is characterized by cytotoxic molecule expression, T/NK-cell derivation, and a predominance of nodal involvement at an advanced stage. It should be differentiated from other EBV+T/NK cell lymphoproliferative disorders, especially extranodal NK/T cell lymphoma.


Assuntos
Infecções por Vírus Epstein-Barr , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma de Células T Periférico/tratamento farmacológico , Adulto , Idoso , Feminino , Herpesvirus Humano 4/genética , Humanos , Células Matadoras Naturais , Masculino , Pessoa de Meia-Idade
12.
Cardiovasc Pathol ; 49: 107264, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32805552

RESUMO

We report a 60-year-old male with fibrin-associated diffuse large B-cell lymphoma (fa-DLBCL) in left atrial myxoma. Echocardiography showed a mass (63 mm × 33 mm) in the left atrium. Histological inspection indicated fa-DLBCL on the surface of atrial myxoma incidentally, together with extensive fibrinous like exudation on myxoma surface. Malignant cells were localized in solid sheets and nests at the peripheral area of the fibrinous exudation which were positive for B-lineage markers (CD20+, CD79a+, PAX-5+) and in situ hybridization of EBV-encoded RNA (EBER). PCR amplification showed clonal rearrangement of immunoglobulin heavy chain (IgH) genes. The patient was still alive with no recurrence in the 35-month follow-up after surgery. We also did a detailed clinicopathological analysis and literature review, which indicated that fa-DLBCL was a heterogeneous entity.


Assuntos
Biomarcadores Tumorais/análise , Fibrina/análise , Neoplasias Cardíacas/patologia , Linfoma Difuso de Grandes Células B/patologia , Mixoma/patologia , Biomarcadores Tumorais/genética , Genes de Cadeia Pesada de Imunoglobulina , Neoplasias Cardíacas/química , Neoplasias Cardíacas/cirurgia , Herpesvirus Humano 4/genética , Humanos , Linfoma Difuso de Grandes Células B/química , Linfoma Difuso de Grandes Células B/cirurgia , Linfoma Difuso de Grandes Células B/virologia , Masculino , Pessoa de Meia-Idade , Mixoma/química , Mixoma/cirurgia , RNA Viral/genética , Resultado do Tratamento
13.
Nat Commun ; 11(1): 3849, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737300

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr Virus (EBV) establish life-long infections and are associated with malignancies. Striking geographic variation in incidence and the fact that virus alone is insufficient to cause disease, suggests other co-factors are involved. Here we present epidemiological analysis and genome-wide association study (GWAS) in 4365 individuals from an African population cohort, to assess the influence of host genetic and non-genetic factors on virus antibody responses. EBV/KSHV co-infection (OR = 5.71(1.58-7.12)), HIV positivity (OR = 2.22(1.32-3.73)) and living in a more rural area (OR = 1.38(1.01-1.89)) are strongly associated with immunogenicity. GWAS reveals associations with KSHV antibody response in the HLA-B/C region (p = 6.64 × 10-09). For EBV, associations are identified for VCA (rs71542439, p = 1.15 × 10-12). Human leucocyte antigen (HLA) and trans-ancestry fine-mapping substantiate that distinct variants in HLA-DQA1 (p = 5.24 × 10-44) are driving associations for EBNA-1 in Africa. This study highlights complex interactions between KSHV and EBV, in addition to distinct genetic architectures resulting in important differences in pathogenesis and transmission.


Assuntos
Anticorpos Antivirais/biossíntese , Resistência à Doença/genética , Infecções por Vírus Epstein-Barr/genética , Infecções por Henipavirus/genética , Interações Hospedeiro-Patógeno/genética , Sarcoma de Kaposi/genética , Adolescente , Adulto , Antígenos Virais/genética , Antígenos Virais/imunologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Coinfecção , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , HIV/genética , HIV/imunologia , HIV/patogenicidade , Cadeias alfa de HLA-DQ/genética , Cadeias alfa de HLA-DQ/imunologia , Infecções por Henipavirus/epidemiologia , Infecções por Henipavirus/imunologia , Infecções por Henipavirus/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/imunologia , Herpesvirus Humano 8/patogenicidade , Interações Hospedeiro-Patógeno/imunologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , População Rural , Sarcoma de Kaposi/epidemiologia , Sarcoma de Kaposi/imunologia , Sarcoma de Kaposi/virologia , Uganda/epidemiologia , População Urbana
14.
PLoS One ; 15(8): e0238062, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841308

RESUMO

This retrospective multicenter cohort study investigated the kinetics (ascending and descending phases) of cytomegalovirus (CMV) and Epstein-Barr virus (EBV)-DNA in whole blood (WB) and plasma samples collected from adult kidney transplant (KT) recipients. CMV-DNA kinetics according to antiviral therapy were investigated. Three hundred twenty-eight paired samples from 42 episodes of CMV infection and 157 paired samples from 26 episodes of EBV infection were analyzed by a single commercial molecular method approved by regulatory agencies for both matrices. CMV-DNAemia followed different kinetics in WB and plasma. In the descending phase of infection, a slower decay of viral load and a higher percentage of CMV-DNA positive samples were observed in plasma versus WB. In the 72.4% of patients receiving antiviral therapy, monitoring with plasma CMV-DNAemia versus WB CMV-DNAemia could delay treatment interruption by 7-14 days. Discontinuation of therapy based on WB monitoring did not result in relapsed infection in any patients. Highly different EBV-DNA kinetics in WB and plasma were observed due to lower positivity in plasma; EBV positive samples with a quantitative result in both blood compartments were observed in only 11.5% of cases. Our results emphasize the potential role of WB as specimen type for post-KT surveillance of both infections for disease prevention and management.


Assuntos
Citomegalovirus/genética , DNA Viral/sangue , Herpesvirus Humano 4/genética , Transplante de Rim , Adulto , Antivirais/farmacologia , Estudos de Coortes , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/fisiologia , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/fisiologia , Humanos , Imunossupressores/farmacologia , Cinética , Estudos Retrospectivos
15.
Oral Dis ; 26 Suppl 1: 158-160, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32862526

RESUMO

We present three cases of oral hairy leukoplakia (OHL) in whom the diagnosis was established by EBV DNA detection in whole saliva. Three HIV-infected patients came to the Oral Medicine Clinic with similar chief complaints of asymptomatic white lesions on the tongue. All patients were diagnosed with suspected OHL and oral thrush also in the first patient. A multiplex PCR DNA microarray was performed to detect EBV DNA in saliva collected by spitting method. All saliva samples showed positive results for EBV DNA, and the definitive diagnosis of OHL was made. Resolution of lesions was found at 1- to 2-month follow-up after treatment with application of acyclovir 5% cream 5 times daily. Additionally, anti-fungal treatment was given to the first patient and anti-retroviral treatment to the first and second patients. EBV is mostly transmitted by asymptomatic shedding into saliva. Therefore, the detection of salivary EBV DNA is useful in establishing a definitive diagnosis of OHL allowing more effective treatment for both HIV-infected patients receiving ART and treatment-naïve patients at any CD4 + count.


Assuntos
Soropositividade para HIV , HIV-1 , Herpesvirus Humano 4 , Leucoplasia Pilosa , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Humanos , Leucoplasia Pilosa/diagnóstico , Leucoplasia Pilosa/virologia , Leucoplasia Oral , Saliva
16.
Nat Genet ; 52(9): 919-930, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32719515

RESUMO

Epstein-Barr virus (EBV) is associated with several human malignancies including 8-10% of gastric cancers (GCs). Genome-wide analysis of 3D chromatin topologies across GC lines, primary tissue and normal gastric samples revealed chromatin domains specific to EBV-positive GC, exhibiting heterochromatin-to-euchromatin transitions and long-range human-viral interactions with non-integrated EBV episomes. EBV infection in vitro suffices to remodel chromatin topology and function at EBV-interacting host genomic loci, converting H3K9me3+ heterochromatin to H3K4me1+/H3K27ac+ bivalency and unleashing latent enhancers to engage and activate nearby GC-related genes (for example TGFBR2 and MZT1). Higher-order epigenotypes of EBV-positive GC thus signify a novel oncogenic paradigm whereby non-integrative viral genomes can directly alter host epigenetic landscapes ('enhancer infestation'), facilitating proto-oncogene activation and tumorigenesis.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/virologia , Cromatina/genética , Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/virologia , Transcrição Genética/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Epigenômica/métodos , Humanos
17.
J Virol ; 94(18)2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32641480

RESUMO

We previously reported that the cellular transcription factor hypoxia-inducible factor 1α (HIF-1α) binds a hypoxia response element (HRE) located within the promoter of Epstein-Barr virus's (EBV's) latent-lytic switch BZLF1 gene, Zp, inducing viral reactivation. In this study, EBV-infected cell lines derived from gastric cancers and Burkitt lymphomas were incubated with HIF-1α-stabilizing drugs: the iron chelator deferoxamine (Desferal [DFO]), a neddylation inhibitor (pevonedistat [MLN-4924]), and a prolyl hydroxylase inhibitor (roxadustat [FG-4592]). DFO and MLN-4924, but not FG-4592, induced accumulation of both lytic EBV proteins and phosphorylated p53 in cell lines that contain a wild-type p53 gene. FG-4592 also failed to activate transcription from Zp in a reporter assay despite inducing accumulation of HIF-1α and transcription from another HRE-containing promoter. Unexpectedly, DFO failed to induce EBV reactivation in cell lines that express mutant or no p53 or when p53 expression was knocked down with short hairpin RNAs (shRNAs). Likewise, HIF-1α failed to activate transcription from Zp when p53 was knocked out by CRISPR-Cas9. Importantly, DFO induced binding of p53 as well as HIF-1α to Zp in chromatin immunoprecipitation (ChIP) assays, but only when the HRE was present. Nutlin-3, a drug known to induce accumulation of phosphorylated p53, synergized with DFO and MLN-4924 in inducing EBV reactivation. Conversely, KU-55933, a drug that inhibits ataxia telangiectasia mutated, thereby preventing p53 phosphorylation, inhibited DFO-induced EBV reactivation. Lastly, activation of Zp transcription by DFO and MLN-4924 mapped to its HRE. Thus, we conclude that induction of BZLF1 gene expression by HIF-1α requires phosphorylated, wild-type p53 as a coactivator, with HIF-1α binding recruiting p53 to Zp.IMPORTANCE EBV, a human herpesvirus, is latently present in most nasopharyngeal carcinomas, Burkitt lymphomas, and some gastric cancers. To develop a lytic-induction therapy for treating patients with EBV-associated cancers, we need a way to efficiently reactivate EBV into lytic replication. EBV's BZLF1 gene product, Zta, usually controls this reactivation switch. We previously showed that HIF-1α binds the BZLF1 gene promoter, inducing Zta synthesis, and HIF-1α-stabilizing drugs can induce EBV reactivation. In this study, we determined which EBV-positive cell lines are reactivated by classes of HIF-1α-stabilizing drugs. We found, unexpectedly, that HIF-1α-stabilizing drugs only induce reactivation when they also induce accumulation of phosphorylated, wild-type p53. Fortunately, p53 phosphorylation can also be provided by drugs such as nutlin-3, leading to synergistic reactivation of EBV. These findings indicate that some HIF-1α-stabilizing drugs may be helpful as part of a lytic-induction therapy for treating patients with EBV-positive malignancies that contain wild-type p53.


Assuntos
Herpesvirus Humano 4/genética , Interações Hospedeiro-Patógeno/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Transativadores/genética , Proteína Supressora de Tumor p53/genética , Linhagem Celular Tumoral , Ciclopentanos/farmacologia , Desferroxamina/farmacologia , Inibidores Enzimáticos/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Regulação da Expressão Gênica , Glicina/análogos & derivados , Glicina/farmacologia , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/crescimento & desenvolvimento , Herpesvirus Humano 4/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/agonistas , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imidazóis/farmacologia , Quelantes de Ferro/farmacologia , Isoquinolinas/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Linfócitos/virologia , Morfolinas/farmacologia , Piperazinas/farmacologia , Inibidores de Prolil-Hidrolase/farmacologia , Regiões Promotoras Genéticas , Ligação Proteica/efeitos dos fármacos , Pirimidinas/farmacologia , Pironas/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Elementos de Resposta , Transdução de Sinais , Transativadores/metabolismo , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Ativação Viral/efeitos dos fármacos
18.
Braz J Infect Dis ; 24(4): 322-329, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32619403

RESUMO

Two types of Epstein Barr virus (EBV1/EBV2) have been shown to infect humans. Although their genomes are similar, the regions containing the EBNA genes differ. This study aimed to characterize the EBV genotypes of infectious mononucleosis (IM) cases in the metropolitan region of Belém, Brazil, from 2005 to 2016. A total of 8295 suspected cases with symptoms/signs of IM were investigated by infectious disease physicians at Evandro Chagas Institute, Health Care Service, from January 2005 to December 2016. Out of the total, 1645 (19.8%) samples had positive results for EBV by enzyme immunoassay and 251 (15.3%) were submitted to polymerase chain reaction (PCR) technique, using the EBNA3C region, in order to determine the type of EBV. Biochemical testing involving aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were also performed. EBV type was identified by PCR in 30.3% (76/251) of individuals; of those, 71.1% (54/76) were classified as EBV1, 17.1% (13/76) as EBV2, and 11.8% (9/76) as EBV1 + EBV2. The main symptoms/signs observed with EBV1 infection were cervical lymphadenopathy (64.8%, 35/54), fever (63%, 34/54), headache (20.4%, 11/54), arthralgia (20.4%, 11/54), and exanthema (18.5%, 10/54). EBV2 infection was detected in all but two age groups, with an average age of 24 years. The most common signs/symptoms of EBV2 were fever (76.9%, 10/13), average duration of 18 days, and lymphadenopathy (69.2%, 9/13). In contrast, EBV1 + EBV2 coinfections were more frequent in those aged five years or less (20.0%, 2/10). The symptoms of EBV1 + EBV2 coinfection included fever (66.7%, 6/9), and cervical lymphadenopathy and headache (33.3%, 3/9) each. The mean values of hepatic enzymes according to type of EBV was significantly different (p < 0.05) in those EBV1 infected over 14 years of age. Thus, this pioneering study, using molecular methods, identified the EBV genotypes in 30.3% of the samples, with circulation of EBV1, EBV2, and EBV1 + EBV2 co-infection in cases of infectious mononucleosis in the northern region of Brazil.


Assuntos
Infecções por Vírus Epstein-Barr/epidemiologia , Herpesvirus Humano 4/genética , Mononucleose Infecciosa/epidemiologia , Adolescente , Adulto , Brasil/epidemiologia , Pré-Escolar , Genótipo , Humanos , Adulto Jovem
19.
J Virol ; 94(17)2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32581094

RESUMO

The Epstein-Barr virus (EBV) BHLF1 gene encodes an abundant linear and several circular RNAs believed to perform noncoding functions during virus replication, although an open reading frame (ORF) is retained among an unknown percentage of EBV isolates. Evidence suggests that BHLF1 is also transcribed during latent infection, which prompted us to investigate the contribution of this locus to latency. Analysis of transcripts transiting BHLF1 revealed that its transcription is widespread among B-cell lines supporting the latency I or III program of EBV protein expression and is more complex than originally presumed. EBV-negative Burkitt lymphoma cell lines infected with either wild-type or two different BHLF1 mutant EBVs were initially indistinguishable in supporting latency III. However, cells infected with BHLF1 - virus ultimately transitioned to the more restrictive latency I program, whereas cells infected with wild-type virus either sustained latency III or transitioned more slowly to latency I. Upon infection of primary B cells, which require latency III for growth in vitro, both BHLF1 - viruses exhibited variably reduced immortalization potential relative to the wild-type virus. Finally, in transfection experiments, efficient protein expression from an intact BHLF1 ORF required the EBV posttranscriptional regulator protein SM, whose expression is limited to the replicative cycle. Thus, one way in which BHLF1 may contribute to latency is through a mechanism, possibly mediated or regulated by a long noncoding RNA, that supports latency III critical for the establishment of EBV latency and lifelong persistence within its host, whereas any retained protein-dependent function of BHLF1 may be restricted to the replication cycle.IMPORTANCE Epstein-Barr virus (EBV) has significant oncogenic potential that is linked to its latent infection of B lymphocytes, during which virus replication is not supported. The establishment of latent infection, which is lifelong and can precede tumor development by years, requires the concerted actions of nearly a dozen EBV proteins and numerous small non-protein-coding RNAs. Elucidating how these EBV products contribute to latency is crucial for understanding EBV's role in specific malignancies and, ultimately, for clinical intervention. Historically, EBV genes that contribute to virus replication have been excluded from consideration of a role in latency, primarily because of the general incompatibility between virus production and cell survival. However, here, we provide evidence that the genetic locus containing one such gene, BHLF1, indeed contributes to key aspects of EBV latency, including its ability to promote the continuous growth of B lymphocytes, thus providing significant new insight into EBV biology and oncogenic potential.


Assuntos
Linfócitos B/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo , Latência Viral/fisiologia , Linfoma de Burkitt , Linhagem Celular , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Regulação Viral da Expressão Gênica , Células HEK293 , Herpesvirus Humano 4/crescimento & desenvolvimento , Humanos , RNA Longo não Codificante/genética , Transcriptoma , Replicação Viral
20.
J Virol ; 94(17)2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32581102

RESUMO

Endemic Burkitt lymphoma (eBL), the most prevalent pediatric cancer in sub-Saharan Africa, is distinguished by its inclusion of Epstein-Barr virus (EBV). In order to better understand the impact of EBV variation in eBL tumorigenesis, we improved viral DNA enrichment methods and generated a total of 98 new EBV genomes from both eBL cases (n = 58) and healthy controls (n = 40) residing in the same geographic region in Kenya. Using our unbiased methods, we found that EBV type 1 was significantly more prevalent in eBL patients (74.5%) than in healthy children (47.5%) (odds ratio = 3.24, 95% confidence interval = 1.36 to 7.71, P = 0.007), as opposed to similar proportions in both groups. Controlling for EBV type, we also performed a genome-wide association study identifying six nonsynonymous variants in the genes EBNA1, EBNA2, BcLF1, and BARF1 that were enriched in eBL patients. In addition, viruses isolated from plasma of eBL patients were identical to their tumor counterparts consistent with circulating viral DNA originating from the tumor. We also detected three intertypic recombinants carrying type 1 EBNA2 and type 2 EBNA3 regions, as well as one novel genome with a 20-kb deletion, resulting in the loss of multiple lytic and virion genes. Comparing EBV types, viral genes displayed differential variation rates as type 1 appeared to be more divergent, while type 2 demonstrated novel substructures. Overall, our findings highlight the complexities of the EBV population structure and provide new insight into viral variation, potentially deepening our understanding of eBL oncogenesis.IMPORTANCE Improved viral enrichment methods conclusively demonstrate EBV type 1 to be more prevalent in eBL patients than in geographically matched healthy controls, which previously underrepresented the prevalence of EBV type 2. Genome-wide association analysis between cases and controls identifies six eBL-associated nonsynonymous variants in EBNA1, EBNA2, BcLF1, and BARF1 genes. Analysis of population structure reveals that EBV type 2 exists as two genomic subgroups and was more commonly found in female than in male eBL patients.


Assuntos
Linfoma de Burkitt/genética , Linfoma de Burkitt/virologia , Infecções por Vírus Epstein-Barr/virologia , Genoma Viral , Herpesvirus Humano 4/genética , Adolescente , Criança , Pré-Escolar , DNA Viral , Infecções por Vírus Epstein-Barr/epidemiologia , Antígenos Nucleares do Vírus Epstein-Barr/genética , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Lactente , Quênia/epidemiologia , Masculino , Razão de Chances , Receptor de Fator Estimulador de Colônias de Macrófagos/genética , Análise de Sequência de DNA , Proteínas Virais/genética
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