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1.
Tumour Biol ; 42(11): 1010428320974247, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33234011

RESUMO

Epstein-Barr virus is an etiologic agent of several malignancies. In this study, we explored the association of Epstein-Barr virus-encoded RNA1 and Epstein-Barr virus latent membrane protein 1 co-expression with osteosarcoma. Epstein-Barr virus-encoded RNA1 expression in tumor cells was quantified using reverse transcriptase polymerase chain reaction and in situ hybridization and Epstein-Barr virus latent membrane protein 1 expression was measured using immunohistochemistry staining. There was a statistically significant association between Epstein-Barr virus latent membrane protein 1 and Epstein-Barr virus-encoded RNA1 co-expression and characteristics of osteosarcoma such as nodal stage (p < 0.04), metastasis (p < 0.04), Ki67 index (p < 0.03), and tumor stage (p < 0.05). Co-expression of Epstein-Barr virus-encoded RNA1 and Epstein-Barr virus latent membrane protein 1 in tumors correlated with advanced osteosarcoma and indicated the aggressiveness of bone sarcoma.


Assuntos
Osteossarcoma/virologia , RNA Viral/metabolismo , Proteínas da Matriz Viral/metabolismo , Adolescente , Adulto , Biomarcadores Tumorais/metabolismo , Criança , Infecções por Vírus Epstein-Barr/mortalidade , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/fisiologia , Humanos , Irã (Geográfico)/epidemiologia , Masculino , Osteossarcoma/mortalidade , Osteossarcoma/patologia , RNA Viral/genética , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
3.
J Virol ; 94(21)2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796077

RESUMO

Epstein-Barr virus (EBV) is one of nine human herpesviruses that persist latently to establish permanent residence in their hosts. Periodic activation into the lytic/replicative phase allows such viruses to propagate and spread, but can also cause disease in the host. This lytic phase is also essential for EBV to cause infectious mononucleosis and cancers, including B lymphocyte-derived Burkitt lymphoma and immunocompromise-associated lymphoproliferative diseases/lymphomas as well as epithelial cell-derived nasopharyngeal cell carcinoma. In the absence of anti-EBV agents, however, therapeutic options for EBV-related diseases are limited. In earlier work, we discovered that through the activities of the viral protein kinase conserved across herpesviruses and two cellular proteins, ATM and KAP1, a lytic cycle amplification loop is established, and disruption of this loop disables the EBV lytic cascade. We therefore devised a high-throughput screening assay, screened a small-molecule-compound library, and identified 17 candidates that impair the release of lytically replicated EBV. The identified compounds will (i) serve as lead compounds or may be modified to inhibit EBV and potentially other herpesviruses, and (ii) be developed into anticancer agents, as functions of KAP1 and ATM are tightly linked to cancer. Importantly, our screening strategy may also be used to screen additional compound libraries for antiherpesviral and anticancer drugs.IMPORTANCE Epstein-Barr virus, which is nearly ubiquitous in humans, is causal to infectious mononucleosis, chronic active EBV infection, and lymphoid and epithelial cancers. However, EBV-specific antiviral agents are not yet available. To aid in the identification of compounds that may be developed as antivirals, we pursued a mechanism-based approach. Since many of these diseases rely on EBV's lytic phase, we developed a high-throughput assay that is able to measure a key step that is essential for successful completion of EBV's lytic cascade. We used this assay to screen a library of small-molecule compounds and identified inhibitors that may be pursued for their anti-EBV and possibly even antiherpesviral potential, as this key mechanism appears to be common to several human herpesviruses. Given the prominent role of this mechanism in both herpesvirus biology and cancer, our screening assay may be used as a platform to identify both antiherpesviral and anticancer drugs.


Assuntos
Antivirais/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Herpesvirus Humano 4/efeitos dos fármacos , Proteínas Quinases/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Transativadores/genética , Proteína 28 com Motivo Tripartido/genética , Antivirais/química , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Linfócitos B/virologia , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/patologia , Linfoma de Burkitt/virologia , Linhagem Celular Tumoral , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Regulação da Expressão Gênica , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/crescimento & desenvolvimento , Herpesvirus Humano 4/metabolismo , Ensaios de Triagem em Larga Escala , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Lisogenia/efeitos dos fármacos , Fosforilação , Proteínas Quinases/metabolismo , Transdução de Sinais , Bibliotecas de Moléculas Pequenas/química , Transativadores/metabolismo , Proteína 28 com Motivo Tripartido/metabolismo , Ativação Viral/efeitos dos fármacos , Latência Viral/efeitos dos fármacos , Replicação Viral
4.
Proc Natl Acad Sci U S A ; 117(25): 14421-14432, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32522871

RESUMO

Epstein-Barr virus (EBV) is a B cell transforming virus that causes B cell malignancies under conditions of immune suppression. EBV orchestrates B cell transformation through its latent membrane proteins (LMPs) and Epstein-Barr nuclear antigens (EBNAs). We here identify secondary mutations in mouse B cell lymphomas induced by LMP1, to predict and identify key functions of other EBV genes during transformation. We find aberrant activation of early B cell factor 1 (EBF1) to promote transformation of LMP1-expressing B cells by inhibiting their differentiation to plasma cells. EBV EBNA3A phenocopies EBF1 activities in LMP1-expressing B cells, promoting transformation while inhibiting differentiation. In cells expressing LMP1 together with LMP2A, EBNA3A only promotes lymphomagenesis when the EBNA2 target Myc is also overexpressed. Collectively, our data support a model where proproliferative activities of LMP1, LMP2A, and EBNA2 in combination with EBNA3A-mediated inhibition of terminal plasma cell differentiation critically control EBV-mediated B cell lymphomagenesis.


Assuntos
Transformação Celular Viral , Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4/patogenicidade , Linfoma de Células B/patologia , Plasmócitos/patologia , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Fibroblastos , Herpesvirus Humano 4/metabolismo , Humanos , Linfoma de Células B/virologia , Camundongos , Camundongos Knockout , Plasmócitos/virologia , Cultura Primária de Células , Transativadores/genética , Transativadores/metabolismo , Proteínas da Matriz Viral/metabolismo , Proteínas Virais/metabolismo
5.
PLoS Pathog ; 16(6): e1008590, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32542010

RESUMO

EBV transforms B cells in vitro and causes human B-cell lymphomas including classical Hodgkin lymphoma (CHL), Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). The EBV latency protein, EBNA2, transcriptionally activates the promoters of all latent viral protein-coding genes expressed in type III EBV latency and is essential for EBV's ability to transform B cells in vitro. However, EBNA2 is not expressed in EBV-infected CHLs and BLs in humans. EBV-positive CHLs have type II latency and are largely driven by the EBV LMP1/LMP2A proteins, while EBV-positive BLs, which usually have type I latency are largely driven by c-Myc translocations, and only express the EBNA1 protein and viral non-coding RNAs. Approximately 15% of human BLs contain naturally occurring EBNA2-deleted viruses that support a form of viral latency known as Wp-restricted (expressing the EBNA-LP, EBNA3A/3B/3C, EBNA1 and BHRF1 proteins), but whether Wp-restricted latency and/or EBNA2-deleted EBV can induce lymphomas in humanized mice, or in the absence of c-Myc translocations, is unknown. Here we show that a naturally occurring EBNA2-deleted EBV strain (P3HR1) isolated from a human BL induces EBV-positive B-cell lymphomas in a subset of infected cord blood-humanized (CBH) mice. Furthermore, we find that P3HR1-infected lymphoma cells support two different viral latency types and phenotypes that are mutually exclusive: 1) Large (often multinucleated), CD30-positive, CD45-negative cells reminiscent of the Reed-Sternberg (RS) cells in CHL that express high levels of LMP1 but not EBNA-LP (consistent with type II viral latency); and 2) smaller monomorphic CD30-negative DLBCL-like cells that express EBNA-LP and EBNA3A but not LMP1 (consistent with Wp-restricted latency). These results reveal that EBNA2 is not absolutely required for EBV to form tumors in CBH mice and suggest that P3HR1 virus can be used to model EBV positive lymphomas with both Wp-restricted and type II latency in vivo.


Assuntos
Infecções por Vírus Epstein-Barr , Antígenos Nucleares do Vírus Epstein-Barr/genética , Deleção de Genes , Herpesvirus Humano 4/fisiologia , Doença de Hodgkin , Linfoma Difuso de Grandes Células B , Proteínas Virais/genética , Latência Viral , Animais , Linhagem Celular , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/patogenicidade , Doença de Hodgkin/genética , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Doença de Hodgkin/virologia , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Camundongos , Proteínas Virais/metabolismo
6.
Ann R Coll Surg Engl ; 102(8): 616-620, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32538153

RESUMO

INTRODUCTION: Upper urinary tract urothelial carcinomas are very rare tumours with different biological behaviours. The Epstein-Barr virus, which is the first known oncogenic virus, is being investigated for various malignant tumours. It is known that this virus is associated with nasopharyngeal carcinoma, as well as multiple haematological malignancies, head and neck and gastric cancers. We aimed to determine the presence of the Epstein-Barr virus in upper urinary tract urothelial carcinomas using chromogenic in situ hybridisation (CISH). MATERIALS AND METHODS: A total of 44 upper urinary tract urothelial carcinomas from two different centres were included. Demographic data and survival rates were obtained from hospital records. One demonstrative paraffin block from each case was stained using Epstein-Barr encoded RNA (EBER) with an automated CISH procedure. The positivity of EBER was statistically analysed for prognostic factors. RESULTS: Among all patients, 38 were male and 6 were female. The mean age of the patients was 65.93 years. At the time of the study, 15 patients had died and 29 were alive. EBER-CISH positivity was found in 13 patients. Four showed strong EBER-CISH expression and nine showed weak expression. EBER-CISH positivity was not statistically related to any of the prognostic factors or to overall survival. DISCUSSION: Although EBER-CISH positivity showed no significant relation with prognostic factors, it was observed in one-third of all cases. Therefore, we think that the Epstein-Barr virus may have a role in the pathogenesis of upper urinary tract urothelial carcinomas. This finding needs to be supported by larger studies.


Assuntos
Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Neoplasias Urológicas , Urotélio , Idoso , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/mortalidade , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/cirurgia , Feminino , Humanos , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Neoplasias Urológicas/mortalidade , Neoplasias Urológicas/patologia , Neoplasias Urológicas/cirurgia , Neoplasias Urológicas/virologia , Urotélio/cirurgia , Urotélio/virologia
7.
J Clin Exp Hematop ; 60(2): 30-36, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32565530

RESUMO

Nodal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (CTL) is a primary nodal peripheral T-cell lymphoma (PTCL) characterized by a cytotoxic phenotype and EBV on the tumor cells. This disease reportedly accounts for 21% of PTCL not otherwise specified (NOS). However, few nodal EBV+ lymphomas have been documented in detail. Nodal EBV+ CTL and nasal-type NK/T-cell lymphoma (NKTL) both exhibit cytotoxic molecule expression and EBV positivity on the tumor cells; however, nodal EBV+ CTL is characterized as a systemic disease without nasopharyngeal involvement, and exhibits a CD8+/CD56- phenotype distinct from NKTL. The clinicopathological uniqueness of nodal EBV+ CTL is further supported by its T-cell origin in most reported cases. In the 2008 WHO classification, it was unclear whether nodal EBV+ CTL should be classified as PTCL or NKTL. However, based on additional data, the 2017 revision classifies nodal EBV+ CTL as PTCL. In the present review, we focus on the clinicopathological characteristics of nodal EBV+ CTL, discuss the relationship between chronic active EBV infection and nodal EBV+ lymphoma, and highlight future perspectives regarding the treatment of this disease.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Linfoma de Células T Periférico/classificação , Linfoma de Células T Periférico/virologia , Linfócitos T Citotóxicos/patologia , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/terapia , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/isolamento & purificação , Humanos , Imunofenotipagem , Linfoma Extranodal de Células T-NK/classificação , Linfoma Extranodal de Células T-NK/patologia , Linfoma Extranodal de Células T-NK/terapia , Linfoma Extranodal de Células T-NK/virologia , Linfoma de Células T Periférico/patologia , Linfoma de Células T Periférico/terapia , Linfócitos T Citotóxicos/virologia , Organização Mundial da Saúde
8.
Int J Lab Hematol ; 42 Suppl 1: 99-106, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32543060

RESUMO

Chronic active Epstein-Barr virus infection of T- and NK-cell type, systemic form, is a rare entity within the spectrum of EBV-driven T- and NK-cell lymphoproliferative disorders. Established diagnostic criteria and a characteristic clinical course help to differentiate it from other closely related EBV-positive neoplasms and clinical states. We present a patient and review the natural history, pathologic features, pathogenesis, and differential diagnosis of this entity.


Assuntos
Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4/metabolismo , Transtornos Linfoproliferativos , Diagnóstico Diferencial , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/patologia , Humanos , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/metabolismo , Transtornos Linfoproliferativos/patologia , Transtornos Linfoproliferativos/virologia , Masculino , Pessoa de Meia-Idade
9.
J Virol ; 94(15)2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32461311

RESUMO

Cellular immunotherapy is a proven approach against Epstein-Barr virus (EBV)-driven lymphoproliferation in recipients of hematopoietic stem cells. Extending the applicability and improving the response rates of such therapy demands improving the knowledge base. We studied 23 healthy donors for specific CD4+ T cell responses against the viral tegument protein BNRF1 and found such T cells in all seropositive donors, establishing BNRF1 as an important immune target in EBV. We identified 18 novel immune epitopes from BNRF1, all of them generated by natural processing of the full-length protein from virus-transformed lymphoblastoid cell lines (LCL). BNRF1-specific CD4+ T cells were measured directly ex vivo by a cytokine-based method, thus providing a tool to study the interaction between immunity and infection in health and disease. T cells of the cytotoxic Th1 type inhibited the proliferation of autologous LCL as well as virus-driven transformation. We infer that they are important in limiting reactivations to subclinical levels during health and reducing virus propagation during disease. The information obtained from this work will feed into data sets that are indispensable in the design of patient-tailored immunotherapeutic approaches, thereby enabling the stride toward broader application of T cell therapy and improving clinical response rates.IMPORTANCE Epstein-Barr virus is carried by most humans and can cause life-threatening diseases. Virus-specific T cells have been used in different clinical settings with variable success rates. One way to improve immunotherapy is to better suit T cell generation protocols to viral targets available in different diseases. BNRF1 is present in viral particles and therefore likely available as a target for T cells in diseases with virus amplification. Here, we studied healthy Epstein-Barr virus (EBV) carriers for BNRF1 immunogenicity and report our results indicating BNRF1 to be a dominant target of the EBV-specific CD4+ T cell response. BNRF1-specific CD4+ T cells were found to be cytotoxic and capable of limiting EBV-driven B cell transformation in vitro The findings of this work contribute to forwarding our understanding of host-virus interactions during health and disease and are expected to find direct application in the generation of specific T cells for immunotherapy.


Assuntos
Epitopos de Linfócito T/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Células Th1/imunologia , Proteínas do Envelope Viral/imunologia , Linhagem Celular Transformada , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/terapia , Feminino , Humanos , Imunoterapia , Masculino , Células Th1/patologia
10.
J Virol ; 94(11)2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32238579

RESUMO

Epstein-Barr virus (EBV) is associated with a number of T-cell diseases, including some peripheral T-cell lymphomas, hemophagocytic lymphohistiocytosis, and chronic active EBV disease. The tropism of EBV for B cells and epithelial cell infection has been well characterized, but infection of T cells has been minimally explored. We have recently shown that the EBV type 2 (EBV-2) strain has the unique ability to infect mature T cells. Utilizing an ex vivo infection model, we sought to understand the viral glycoprotein and cellular receptor required for EBV-2 infection of T cells. Here, using a neutralizing-antibody assay, we found that viral gp350 and complement receptor 2 (CD21) are required for CD3+ T-cell infection. Using the HB5 anti-CD21 antibody clone but not the Bly-4 anti-CD21 antibody clone, we detected expression of CD21 on both CD4+ and CD8+ T cells, with the highest expression on naive CD4 and CD8+ T-cell subsets. Using CRISPR to knock out CD21, we demonstrated that CD21 is necessary for EBV entry into the Jurkat T-cell line. Together, these results indicate that EBV uses the same viral glycoprotein and cellular receptor for both T- and B-cell infection.IMPORTANCE Epstein-Barr virus (EBV) has a well-described tropism for B cells and epithelial cells. Recently, we described the ability of a second strain of EBV, EBV type 2, to infect mature peripheral T cells. Using a neutralizing antibody assay, we determined that EBV uses the viral glycoprotein gp350 and the cellular protein CD21 to gain entry into mature peripheral T cells. CRISPR-Cas9 deletion of CD21 on the Jurkat T-cell line confirmed that CD21 is required for EBV infection. This study has broad implications, as we have defined a function for CD21 on mature peripheral T cells, i.e., as a receptor for EBV. In addition, the requirement for gp350 for T-cell entry has implications for EBV vaccine studies currently targeting the gp350 glycoprotein to prevent EBV-associated diseases.


Assuntos
Linfócitos B/metabolismo , Infecções por Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/metabolismo , Receptores de Complemento 3d/metabolismo , Linfócitos T/metabolismo , Internalização do Vírus , Adulto , Linfócitos B/patologia , Linfócitos B/virologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/patologia , Feminino , Deleção de Genes , Herpesvirus Humano 4/genética , Humanos , Masculino , Receptores de Complemento 3d/genética , Linfócitos T/patologia , Linfócitos T/virologia
11.
Am J Surg Pathol ; 44(8): 1061-1072, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32317607

RESUMO

Systemic Epstein-Barr virus-positive T-cell and natural killer (NK)-cell lymphoproliferative diseases of childhood are a group of lethal diseases mostly affecting children and young adults. The Ohshima Grading System and the 2017 World Health Organization (WHO) classification have been used for classifying this spectrum, but these systems have not been validated externally and compared. Therefore, we examined 36 cases of systemic Epstein-Barr virus-positive T-cell and NK-cell lymphoproliferative diseases of childhood with long-term follow-up, from Southwest China, to systematically summarize the clinicopathologic features and to validate and compare the Ohshima Grading System and the 2017 WHO classification in discrimination ability, predictive accuracy, concordance indices, and explained variation. Clinically, our cohort showed severe manifestations and poor prognoses. Morphologically, the hematopoietic and lymphoid specimens showed proliferation of small-sized to medium-sized bland-looking lymphocytes that might mask disease severity, whereas other extranodal lesions showed a disorganized to obliterated architecture infiltrated by medium-sized to large-sized, subtle to obvious atypical cells, which may mimic extranodal NK/T-cell lymphoma. Immunophenotypically, our cases mainly originate from CD8 αß T cells. Therefore, clinical and pathologic features should be equally considered to avoid missed diagnosis or misdiagnosis. In addition, the 2017 WHO classification shows a flexible grasp of pathologic features, thus classifying some cases (polymorphic and monoclonal cases with fulminant course) more reasonably; thereby, it showed statistically improved results compared with the Ohshima Grading System. However, underestimating the risk of some polyclonal cases and imprecisely discriminating monoclonal cases at diagnosis are common dilemmas in both systems. Therefore, the construction of a comprehensive grading algorithm for improved prognostic value and precise diagnosis requires additional studies.


Assuntos
Infecções por Vírus Epstein-Barr/classificação , Herpesvirus Humano 4/genética , Células Matadoras Naturais/imunologia , Transtornos Linfoproliferativos/classificação , Linfócitos T/imunologia , Adolescente , Adulto , Idade de Início , Proliferação de Células , Criança , Pré-Escolar , China , Bases de Dados Factuais , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Genes Codificadores da Cadeia alfa de Receptores de Linfócitos T , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T , Humanos , Lactente , Células Matadoras Naturais/patologia , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia , Transtornos Linfoproliferativos/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Viral/genética , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Linfócitos T/patologia , Fatores de Tempo , Adulto Jovem
12.
Am J Surg Pathol ; 44(9): 1173-1183, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32349049

RESUMO

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoproliferation encompasses a broad range of clinicopathologic findings, including specific subtypes, for example, EBV mucocutaneous ulcer. Here we reassessed 36 cases of primary EBV diffuse large B-cell lymphomas (16 men and 20 women; median age, 69.5 y; range, 35 to 84 y), including 8 immunosuppressed patients (Lugano stage II-IV; median age, 74 y), 7 nonimmunosuppressed patients with stage I disease (median age, 69 y), and 21 nonimmunosuppressed patients with stage II-IV disease (median age, 69 y). All immunosuppressed patients exhibited iatrogenic immunodeficiency and an ulcerative appearance, with ulcer sites including the stomach (1 patient), small intestine (6 patients), and rectum (1 patient). Four patients were in the setting of treated lymphoma-associated immunosuppression. Immunosuppressed patients had higher incidences of intestinal involvement (P=0.001) and perforation (n=2) compared with advanced stage nonimmunosuppressed patients. Among nonimmunosuppressed stage I patients, lesions were restricted to the stomach, none showed multiple lesions or elevated serum lactate dehydrogenase, and the overall survival curve plateaued, although it was not statistically significant (P=0.0581). One nonimmunosuppressed stage I patient with a polypoid lesion exhibited spontaneous regression within 2 months after diagnosis, while another with bulky disease pursued an aggressive clinical course. Nonimmunosuppressed stage I cases without bulky masses may be considered EBV mucocutaneous ulcer with local progression. Our results demonstrated that primary EBV gastrointestinal diffuse large B-cell lymphoma could be delineated into 3 groups based on immune status and clinical stage, revealing distinguishing features useful as a pragmatic guide for diagnostic and therapeutic approaches.


Assuntos
Infecções por Vírus Epstein-Barr/virologia , Neoplasias Gastrointestinais/virologia , Herpesvirus Humano 4/genética , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Linfoma Difuso de Grandes Células B/virologia , RNA Viral/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/terapia , Feminino , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/terapia , Herpesvirus Humano 4/imunologia , Humanos , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco
13.
J Virol ; 94(11)2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32213613

RESUMO

Interferon alpha (IFN-α) and IFN-ß are type I IFNs that are induced by virus infection and are important in the host's innate antiviral response. EBV infection activates multiple cell signaling pathways, resulting in the production of type I IFN which inhibits EBV infection and virus-induced B-cell transformation. We reported previously that EBV tegument protein BGLF2 activates p38 and enhances EBV reactivation. To further understand the role of BGLF2 in EBV infection, we used mass spectrometry to identify cellular proteins that interact with BGLF2. We found that BGLF2 binds to Tyk2 and confirmed this interaction by coimmunoprecipitation. BGLF2 blocked type I IFN-induced Tyk2, STAT1, and STAT3 phosphorylation and the expression of IFN-stimulated genes (ISGs) IRF1, IRF7, and MxA. In contrast, BGLF2 did not inhibit STAT1 phosphorylation induced by IFN-γ. Deletion of the carboxyl-terminal 66 amino acids of BGLF2 reduced the ability of the protein to repress type I IFN signaling. Treatment of gastric carcinoma and Raji cells with IFN-α blocked BZLF1 expression and EBV reactivation; however, expression of BGLF2 reduced the ability of IFN-α to inhibit BZLF1 expression and enhanced EBV reactivation. In summary, EBV BGLF2 interacts with Tyk2, inhibiting Tyk2, STAT1, and STAT3 phosphorylation and impairs type I IFN signaling; BGLF2 also counteracts the ability of IFN-α to suppress EBV reactivation.IMPORTANCE Type I interferons are important for controlling virus infection. We have found that the Epstein-Barr virus (EBV) BGLF2 tegument protein binds to a protein in the type I interferon signaling pathway Tyk2 and inhibits the expression of genes induced by type I interferons. Treatment of EBV-infected cells with type I interferon inhibits reactivation of the virus, while expression of EBV BGLF2 reduces the ability of type I interferon to inhibit virus reactivation. Thus, a tegument protein delivered to cells during virus infection inhibits the host's antiviral response and promotes virus reactivation of latently infected cells. Therefore, EBV BGLF2 might protect virus-infected cells from the type I interferon response in cells undergoing lytic virus replication.


Assuntos
Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/fisiologia , Interferon Tipo I/imunologia , Transdução de Sinais/imunologia , Proteínas Virais de Fusão/imunologia , Ativação Viral/imunologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/patologia , Células HEK293 , Humanos , Fator Regulador 1 de Interferon/genética , Fator Regulador 1 de Interferon/imunologia , Fator Regulador 7 de Interferon/genética , Fator Regulador 7 de Interferon/imunologia , Interferon Tipo I/genética , Interferon gama/genética , Interferon gama/imunologia , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/genética , TYK2 Quinase/genética , TYK2 Quinase/imunologia , Proteínas Virais de Fusão/genética , Ativação Viral/genética
14.
Am J Case Rep ; 21: e921269, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32176677

RESUMO

BACKGROUND Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) is a rare subtype of B-cell neoplasm that can have diverse presentations. When it involves the pancreas (i.e., pancreatic lymphoma), it can mimic metastatic pancreatic adenocarcinoma. Pancreatic lymphoma and adenocarcinoma often have similar clinical, laboratory, and radiographic features making the distinction challenging without pathological tissue examination. The differentiation of these 2 entities is important as the prognosis of pancreatic lymphoma is certainly more favorable with a chance of cure with chemoimmunotherapy. CASE REPORT We present an unusual case of EBV-positive DLBCL involving the pancreas that was initially believed to be metastatic pancreatic adenocarcinoma. The patient was treated with chemoimmunotherapy and had a remarkable response. This is the first known case of EBV-positive DLBCL involving the pancreas that was successfully treated with chemoimmunotherapy. CONCLUSIONS EBV-positive DLBCL can have diverse presentations, including a pancreatic mass with multi-organ involvement, which mimics metastatic pancreatic adenocarcinoma. The prognosis of EBV-positive DLBCL is thought to be worse than that of EBV-negative tumors. However, it remains certainly superior to that of its adenocarcinoma counterpart with conventional chemoimmunotherapy.


Assuntos
Infecções por Vírus Epstein-Barr/patologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/terapia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia , Adenocarcinoma/diagnóstico , Terapia Combinada , Diagnóstico Diferencial , Tratamento Farmacológico , Humanos , Imunoterapia , Linfoma Difuso de Grandes Células B/virologia , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/virologia , Prognóstico , Resultado do Tratamento
15.
Exp Cell Res ; 390(2): 111968, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32197932

RESUMO

EBV-associated gastric carcinoma (EBVaGC) is accompanied by massive lymphocyte infiltration, but therapy resistance and tumor progression still occur in patients with EBVaGC. Cancer stem cells (CSCs) are reported to possess immunomodulatory ability that allows them to resist immune-mediated rejection for many tumor types. However, whether and how CSCs in EBVaGC exhibit immunosuppression has not yet been elucidated. We isolated CSC-like sphere-forming cells (SFCs) from EBVaGC cell line SNU-719 using the cancer sphere method. We validated their CSC-associated properties in the expression of the epithelial-mesenchymal transition (EMT)-related genes, the ability to form colonies, and resistance to chemotherapy drug-induced apoptosis and explored their immunomodulatory ability using the coculture system with PBMC (peripheral blood mononuclear cell). These CSC-like SFCs were CD44+CD24-/low and were more tumorigenic than the parental SNU-719 cells in the xenograft mouse model. Remarkably, in the tumor-PBMC co-culturing experiments, these EBVaGC SFCs demonstrated profound immunosuppression by inhibiting the proliferation of PBMCs and T cell activation as well as inducing the generation of regulatory T cells (Tregs). Furthermore, the induction of Tregs was partially dependent on prostaglandin E2 (PGE2) produced from SFCs. Moreover, the presence of high CD44+CD24-/low cells in tumor tissues predicted a decreased disease-free survival in patients with EBVaGC. Our study collectively confirmed the existence and immune resistance of CSCs in EBVaGC and offers new insights into the development of novel anti-EBVaGC strategies by targeting CSCs.


Assuntos
Antígeno CD24/imunologia , Carcinoma/imunologia , Dinoprostona/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Regulação Neoplásica da Expressão Gênica , Receptores de Hialuronatos/imunologia , Neoplasias Gástricas/imunologia , Adulto , Idoso , Animais , Antígeno CD24/genética , Carcinoma/complicações , Carcinoma/genética , Carcinoma/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Dinoprostona/biossíntese , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/imunologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/patologia , Feminino , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/patogenicidade , Humanos , Receptores de Hialuronatos/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Transdução de Sinais , Esferoides Celulares/imunologia , Esferoides Celulares/patologia , Neoplasias Gástricas/complicações , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Linfócitos T Reguladores/virologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Cancer Lett ; 478: 122-132, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32165272

RESUMO

Nasopharyngeal carcinoma (NPC) is a unique head and neck malignancy with highly metastatic cell-biological characteristics, for which latent EBV-infection is responsible. Our earlier studies showed that EGF-stimulated Ca2+ signaling via store-operated Ca2+ entry (SOCE) was amplified in NPC cells expressing EBV-encoded LMP1, thus contributing to EBV-enhanced metastatic capacities. However, the pathway through which EBV modulates cytosolic Ca2+ signaling still remains unclear. Here, we demonstrated that EBV-infection amplified EGF-stimulated Ca2+ responses through the promotion of intracellular aggregation of STIM1, which serves as a Ca2+ sensor to activate SOCE. Blockage of EBV-remodeled Ca2+ signaling by STIM1-silencing inhibited cell migration by interrupting epithelial-mesenchymal transition (EMT) in vitro, and suppressed tumor dissemination in zebrafish and lymph node metastasis in mice. In addition, STIM1 expression was upregulated in primary NPC tissues compared with normal nasopharyngeal epithelium and stronger among the patients with advanced lymph node metastatic disease (N2-3 stage). Our findings thus indicate that EBV promotes metastatic potential by enhancing STIM1-dependent Ca2+ signaling that manipulates EMT in NPC cells. EBV-modulated Ca2+ signaling could serve as a candidate anti-metastatic target for NPC treatment.


Assuntos
Infecções por Vírus Epstein-Barr/patologia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/virologia , Proteínas de Neoplasias/metabolismo , Molécula 1 de Interação Estromal/metabolismo , Regulação para Cima , Animais , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fator de Crescimento Epidérmico/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/metabolismo , Feminino , Humanos , Camundongos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Metástase Neoplásica , Proteínas de Neoplasias/genética , Transplante de Neoplasias , Molécula 1 de Interação Estromal/genética , Peixe-Zebra
17.
Cancer Causes Control ; 31(4): 365-375, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32112173

RESUMO

PURPOSE: Although infection with high-risk human papillomavirus (HPV) is a prerequisite for cervical cancer development, HPV infection is not sufficient to promote cancer in the majority of infected women. We tested the hypothesis that human herpesviruses might cooperate with HPV to promote the development of cervical dysplasia, an early indicator of cervical cancer development. METHODS: This study used archived specimens from a cohort of human immunodeficiency virus (HIV)-seropositive women seeking gynecological care at the Medical Center of New Orleans, Louisiana. Viral DNA was detected by PCR amplification and risk of abnormal cervical cytology was determined in relation to virus test results. RESULTS: Consensus human herpesvirus PCR with herpes speciation by restriction endonuclease digestion revealed Epstein-Barr virus (EBV) to be the most prevalent herpesvirus in cervicovaginal lavage specimens. Further analysis using an EBV-specific PCR assay and cervical swab specimens demonstrated an approximately fourfold increased risk of abnormal cervical cytology in women testing positive for cervical EBV and high-risk HPV compared to women testing positive for high-risk HPV alone. This relationship was independent of markers of advancing HIV disease. CONCLUSION: Cervical shedding of EBV appears to predict a greater risk of cervical dysplasia in HIV-infected women with a high-risk HPV infection.


Assuntos
Infecções por Vírus Epstein-Barr/patologia , Infecções por HIV/patologia , Herpesvirus Humano 4/isolamento & purificação , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/patologia , Displasia do Colo do Útero/virologia , Adulto , Neoplasia Intraepitelial Cervical/epidemiologia , Neoplasia Intraepitelial Cervical/patologia , Neoplasia Intraepitelial Cervical/virologia , Estudos de Coortes , DNA Viral/análise , DNA Viral/genética , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Infecções por HIV/virologia , Herpesvirus Humano 4/genética , Humanos , Louisiana/epidemiologia , Pessoa de Meia-Idade , Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase , Displasia do Colo do Útero/epidemiologia , Displasia do Colo do Útero/patologia , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia
18.
Indian J Pathol Microbiol ; 63(1): 78-82, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32031127

RESUMO

Introduction: Epstein-Barr Virus (EBV)-associated systemic T-cell lymphoproliferative disorder of childhood is a rare but severe manifestation of chronic EBV infection. Despite several case reports characterizing this rare hematological neoplasm, the literature describes extensive heterogeneity in the presentation of this disease. Case presentation: Here we present a complete autopsy of a 16-year-old girl who ultimately succumbed to EBV-associated systemic T-cell lymphoproliferative disorder of childhood. Her clinical presentation demonstrated a non-specific pharyngitis with positive mono spot test, evolving into fulminant multi-organ failure, disseminated intravascular coagulopathy, sepsis, and ultimately death. Conclusions: Post-mortem findings included extensive hemorrhage, and infiltration of the liver, spleen, lymph nodes and bone marrow with neoplastic T-cells. There was extensive hemophagocytic lymphohistiocytosis (HLH) within these organs, suggesting overlap between the EBV-associated systemic T-cell lymphoproliferative disorder of childhood and EBV-associated HLH. We hope these findings provide a more comprehensive overview of several possible manifestations of EBV-associated systemic T-cell lymphoproliferative disorder of childhood.


Assuntos
Autopsia , Infecções por Vírus Epstein-Barr/patologia , Linfo-Histiocitose Hemofagocítica/patologia , Transtornos Linfoproliferativos/patologia , Adolescente , Biópsia , Medula Óssea/patologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Evolução Fatal , Feminino , Humanos , Linfonodos/patologia , Linfo-Histiocitose Hemofagocítica/virologia , Transtornos Linfoproliferativos/virologia , Insuficiência de Múltiplos Órgãos , Sepse , Linfócitos T/patologia
20.
Future Oncol ; 16(6): 187-197, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31989840

RESUMO

Aim: To identify the methylated-differentially expressed genes (MDEGs) that may serve as diagnostic markers and therapeutic targets in Epstein-Barr virus-associated gastric cancer (EBVaGC) and to explore the methylation-based pathways for elucidating biological mechanisms of EBVaGC. Materials & methods: Gene expression and methylation profiles were downloaded from GEO database. MDEGs were identified by GEO2R. Pathway enrichment analyses were conducted based on DAVID database. Hub genes were identified by Cytoscape, which were further verified by The Cancer Genome Atlas database. Results: A total of 367 hypermethylated, lowly expressed genes were enriched in specific patterns of cell differentiation. 31 hypomethylated, highly expressed genes demonstrated enrichment in regulation of immune system process. After validation using The Cancer Genome Atlas database, seven genes were confirmed to be significantly different hub genes in EBVaGC. Conclusion: EBVaGC-specific MDEGs and pathways can be served as potential biomarkers for precise diagnosis and treatment of EBVaGC and provide novel insights into the mechanisms involved.


Assuntos
Biomarcadores Tumorais/genética , Epigênese Genética , Infecções por Vírus Epstein-Barr/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/virologia , Biomarcadores Tumorais/metabolismo , Biologia Computacional , Metilação de DNA , Bases de Dados Genéticas , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Herpesvirus Humano 4 , Humanos , Mapas de Interação de Proteínas , Reprodutibilidade dos Testes , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
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