Research Advances in Infectious Mononucleosis Caused by Epstein-Barr Virus

Infectious mononucleosis (IM), primarily caused by the Epstein-Barr virus (EBV), manifests as the classic triad of fever, pharyngitis, and cervical lymphadenopathy. Severe cases may involve organ damage, most commonly affecting the liver. Diagnosis relies on a combination of clinical presentation and laboratory parameters, with commonly used indicators including EBV-specific antibodies, EBV-DNA load, and the ratio of atypical lymphocytes. Treatment primarily involves symptomatic supportive care, with a cautious approach to the routine use of antiviral medications. In recent years, significant research in traditional Chinese medicine has been conducted in China, showing promising advancements. This article provides a comprehensive review of EBV-induced infectious mononucleosis, offering insights for clinical diagnosis and treatment.

Epstein-Barr病毒相关淋巴上皮瘤样肝内胆管癌3例并文献复习

肝淋巴上皮瘤样癌(Lymphoepithelioma-like carcinoma,LELC)是一种极其罕见的恶性肿瘤,其特点是未分化的恶性上皮细胞及明显的淋巴浸润。肝LELC主要包括淋巴上皮瘤样肝细胞癌(lymphoepithelioma-like hepatocellularcarcinoma,LEL-HCC)和淋巴上皮瘤样肝内胆管癌(lymphoepithelioma-likeintrahepatic cholangiocarcinoma,LEL-CC)。EB病毒(Epstein-Barr virus,EBV)感染被认为是LELC癌变的重要因素。中南大学湘雅医院自2005年以来共收治3例EBV相关LEL-CC患者,CT均提示肝脏肿块,经手术切除后,3例患者EBV编码的RNA(EBV-encoded RNA,EBER)和CK19表达均为阳性,病理学证实为EBV相关的LEL-CC。2例患者术后预后良好,1例患者术后接受相关免疫治疗及化学治疗。结合现有文献分析,笔者认为可将肝LELC纳入肝肿瘤的分类,这将为肝LELC的精准诊断及治疗提供新思路。

Epstein-Barr病毒与肝损伤相关性的研究进展

EB病毒(Epstein-Barr Virus,EBV)作为常见的非嗜肝DNA病毒之一,早已被研究证实可以导致肝脏损伤(Liver injury)并引起肝功能异常,且已成为临床医生对肝功能异常患者筛查的重要指标之一。但目前尚缺乏对既往有关其感染所致肝损伤的研究成果的有效整合。本文通过梳理相关文献系统、全面探讨EBV与肝损伤相关性的研究进展,包括EBV概述、感染的现状、传播方式、所致疾病类型、其致肝损伤可能的机制和对临床诊疗的影响及EBV相关性肝损伤未来的研究方向。本文表明EBV感染所致肝损伤可能持续存在并导致严重后果,为全球带来巨大的疾病负担。因此,临床医生必须对其予以足够的重视,以期早期识别,并尽早采取有效措施使患者能最大获益。

Mucocutaneous ulcer positive for Epstein–Barr virus,misdiagnosed as a small bowel adenocarcinoma:A case report

BACKGROUND Epstein–Barr virus(EBV)-positive mucocutaneous ulcers(MCUs)are an uncommon disorder characterized by ulcerative lesions in the skin,oral cavity or gastrointestinal tract in patients with iatrogenic or aging-induced immunosuppression.The nonspecific lesions are difficult to differentiate from small bowel adenocarcinomas.We present the case of a 69-year-old woman who was initially misdiagnosed with a small bowel adenocarcinoma but was later surgically diagnosed with and treated for EBV-MCU.Through this case,we aim to emphasize the importance of accurately distinguishing between the two conditions.CASE SUMMARY The patient presented with an incidental finding of a small bowel tumor during computed tomography(CT)examination performed for hematuria.The CT scan showed irregular thickening of the distal ileum,which was suggestive of a malignant small bowel tumor.An exploratory laparotomy revealed an 8-cm mass in the distal ileum;thus,a segment of the small intestine,including the mass,was resected.Histopathological analysis revealed an ulceroinfiltrative mass-like lesion with luminal narrowing,marked inflammatory cell infiltration,and large atypical lymphoid cells(positive for EBV-encoded small RNA).A final diagnosis of an EBV-MCU was established.The postoperative course was uneventful,and the patient was discharged on postoperative day 7.The patient remained recurrencefree until 12 mo after surgery.CONCLUSION This case highlights the diagnostic challenges for EBV-MCUs and emphasizes the importance of comprehensive evaluation and accurate histopathological analysis.

Epstein-Barr病毒相关噬血细胞综合征患者细胞因子/趋化因子表达谱及其临床意义

目的:观察Epstein-Barr病毒(EBV)相关噬血细胞综合征(HLH)患者细胞因子/趋化因子表达谱,探讨其对生存结局的预测效能。方法:采用多细胞因子检测方法对EBV相关HLH患者、EBV感染者和对照者血清中38种细胞因子/趋化因子进行检测,比较各组之间细胞因子/趋化因子的表达差异。比较EBV相关HLH患者活动期和缓解期细胞因子/趋化因子的表达变化,评估其对生存结局的预测效能。结果:EBV相关HLH患者血清干扰素-α2(IFN-α2)、白细胞介素(IL)-6和IL-7水平分别为33.67(23.23-68.78)pg/ml、(74.95±25.53)pg/ml、35.35(19.50-63.55)pg/ml,显著高于EBV感染者[IFN-α2:16.07(9.87-29.63);IL-6:55.91±20.29;IL-7:20.40(13.35-31.40)]和对照者[IFN-α2:11.02(4.67-21.25);IL-6:42.64±13.41;IL-7:16.95(14.95-33.78)](均P<0.05)。EBV相关HLH患者血清IL-8、IL-9和巨噬细胞来源趋化因子(MDC)水平分别为11.00(7.50-15.27)pg/ml、81.30(40.79-111.0)pg/ml和(512.6±128.7)pg/ml,均显著高于对照者[IL-8:6.80(5.56-8.38);IL-9:41.30(29.82-67.91);MDC:384.1±156.6](均P<0.05),但与EBV感染者比较无统计学差异(P>0.05)。对EBV相关HLH患者存活组和死亡组血清IFN-α2、IL-6、IL-7、IL-8、IL-9、MDC水平进行ROC曲线分析,曲线下面积分别为0.781、0.778、0.633、0.805、0.562、0.657,P值分别为0.019、0.021、0.269、0.015、0.607、0.190,其中IFN-α2、IL-6、IL-8生存结局预测效能良好。EBV相关HLH患者缓解期血清IFN-α2、IL-6、MDC水平显著低于疾病活动期(P<0.05),而IL-7、IL-8、IL-9水平在疾病活动期和缓解期患者中的差异无统计学意义(P>0.05)。结论:IFN-α2、IL-6、IL-7、IL-8、IL-9、MDC可能参与了EBV相关HLH的发病过程。

Prognostic value of plasma Epstein-Barr virus DNA level during posttreatment follow-up in the patients with nasopharyngeal carcinoma having undergone intensity-modulated radiotherapy

Background: The value of Epstein-Barr virus(EBV) DNA assay during posttreatment follow-up of the patients with nasopharyngeal carcinoma(NPC) presenting with different pretreatment plasma EBV DNA levels remains unclear. In the present study, we aimed to evaluate the prognostic value of plasma EBV DNA assay during posttreatment followup in the patients with NPC who have undergone intensity-modulated radiotherapy.Methods: The medical records of 385 NPC patients treated with intensity-modulated radiotherapy between November 2009 and February 2012 were reviewed. All patients underwent plasma EBV DNA assays before treatment, within3 months after treatment, and then every 3-12 months during posttreatment follow-up period. The recurrence rates for patients with different pretreatment and posttreatment follow-up plasma EBV DNA levels were analyzed.Results: Of the 385 patients, 267(69.4%) had detectable pretreatment plasma EBV DNA(> 0 copy/mL) and 93(24.2%) had detectable posttreatment EBV DNA during a median follow-up of 52.8 months(range 9.3-73.8 months).Detectable EBV DNA during posttreatment follow-up was found in 14.4%(17/118) and 28.5%(76/267) of patients with undetectable and detectable pretreatment EBV DNA, respectively, and was significantly associated with tumor recurrence in both patient groups. EBV DNA was detectable in 12.8%(40/313) of patients who remained disease-free,56.4%(22/39) of patients with locoregional recurrence alone, and 93.9%(31/33) of patients with distant metastasis as the first recurrence event(P < 0.001); 6.5%(19/292) of patients with undetectable EBV DNA and 57.0%(53/93) of patient with detectable EBV DNA during posttreatment follow-up experienced tumor recurrence. Compared with other cut-off values, the cut-off value of 0 copy/mL for EBV DNA during posttreatment follow-up had the highest area under the ROC curve(AUC) value(0.804,95% confidence interval 0.741-0.868) for predicting tumor recurrence(sensitivity, specificity, and accuracy: 73.6%, 87.2%, and 84.7%, respectively).Conclusion: Plasma EBV DNA level during posttreatment follow-up is a good marker for predicting distant metastasis but not locoregional recurrence in the patients with NPC irrespective of the pretreatment EBV DNA levels.

Prognostic values of the integrated model incorporating the volume of metastatic regional cervical lymph node and pretreatment serum Epstein-Barr virus DNA copy number in predicting distant metastasis in patients with N1 nasopharyngeal carcinoma

Background: According to the 7 th edition of the American Joint Committee on Cancer(AJCC) staging system, over50% of patients with nasopharyngeal carcinoma(NPC) have N1 disease at initial diagnosis. However, patients with N1 NPC are relatively under-researched, and the metastasis risk of this group is not well-stratified. This study aimed to evaluate the prognostic values of gross tumor volume of metastatic regional lymph node(GTVnd) and pretreatment serum copy number of Epstein-Barr virus(EBV) DNA in predicting distant metastasis of patients with N1 NPC, and to develop an integrated prognostic model that incorporates GTVnd and EBV DNA copy number for this group of patients.Methods: The medical records of 787 newly diagnosed patients with nonmetastatic, histologically proven N1 NPC who were treated at Sun Yat-sen University Cancer Center between November 2009 and February 2012 were analyzed. Computed tomography-derived GTVnd was measured using the summation-of-area technique. Blood samples were collected before treatment to quantify plasma EBV DNA. The receiver operating characteristic(ROC) curve analysis was used to evaluate the cut-off point for GTVnd, and the area under the ROC curve was used to assess the predicted validity of GTVnd. The survival rates were assessed by Kaplan-Meier analysis, and the survival curves were compared using a log-rank test. Multivariate analysis was conducted using the Cox proportional hazard regression model.Results: The 5-year distant metastasis-free survival(DMFS) rates for patients with GTVnd > 18.9 vs.≤ 18.9 mL were82.2% vs. 93.2%(P < 0.001), and for patients with EBV DNA copy number > 4000 vs. < 4000 copies/mL were 83.5% vs.93.9%(P < 0.001). After adjusting for GTVnd, EBV DNA copy number, and T category in the Cox regression model, both GTVnd > 18.9 mL and EBV DNA copy number > 4000 copies/mL were significantly associated with poor prognosis(both P < 0.05). According to combination of GTVnd and EBV DNA copy number, all patients were divided into low-,moderate-, and high-risk groups, with the 5-year DMFS rates of 96.1,87.4, and 73.8%, respectively(P < 0.001). Multivariate analysis confirmed the prognostic value of this model for distant metastatic risk stratification(hazard ratio [HR],4.17; 95% confidence interval [CI] 2.34-7.59; P < 0.001).Conclusions: GTVnd and serum EBV DNA copy number are independent prognostic factors for predicting distant metastasis in NPC patients with N1 disease. The prognostic model incorporating GTVnd and EBV DNA copy number may improve metastatic risk stratification for this group of patients.

Epstein Barr virus-positive mucocutaneous ulcer of thecolon associated Hodgkin lymphoma in Crohn＇s disease

Epstein Barr virus （EBV） positive mucocutaneous ulcers（EBVMCU） form part of a spectrum of EBV-associatedlymphoproliferative disease. They have been reportedin the setting of immunosenescence and iatrogenicimmunosuppression, affecting the oropharyngeal mucosa,skin and gastrointestinal tract （GIT）. Case reports andseries to date suggest a benign natural history respondingto conservative management, particularly in the GIT. Wereport an unusual case of EBVMCU in the colon, arisingin the setting of immunosuppression in the treatment ofCrohn＇s disease, with progression to Hodgkin lymphoma18 mo after cessation of infliximab. The patient presentedwith multiple areas of segmental colonic ulceration,histologically showing a polymorphous infiltrate withEBV positive Reed-Sternberg-like cells. A diagnosisof EBVMCU was made. The ulcers failed to regressupon cessation of infliximab and methotrexate for 18mo. Following commencement of prednisolone for herCrohn＇s disease, the patient developed widespreadHodgkin lymphoma which ultimately presented as alife-threatening lower GIT bleed requiring emergencycolectomy. This is the first report of progression ofEBVMCU to Hodgkin lymphoma, in the setting of ongoingiatrogenic immunosuppression and inflammatory boweldisease.

Expression of Epstein-Barr virus genes in EBV-associated gastric carcinomas

AIM: To understand the expression of latent and lytic genes of Epstein-Barr virus (EBV) in EBV-associated gastric carcinoma (EBVaGC) and to explore the relationship between EBV-encoded genes and development of EBVaGC at molecular level.METHODS: One hundred and seventy-two gastric carcinoma tissues and 172 corresponding para-carcinoma tissues were tested for EBV genome by polymerase chain reaction (PCR)-Southern blotting. EBV-encoded small RNA (EBER)1 of the PCR positive specimens was detected by in situ hybridization (ISH). Gastric carcinomas with positive EBER1signals were classified as EBVaGCs. RT-PCR and Southern hybridization were applied to the detection of expression of nuclear antigen (EBNA) promoters (Qp, Wp and Cp),EBNA 1 and EBNA 2, latent membrane proteins (LMP) 1,2A and 2B and lytic genes (immediate early genes BZLF1and BRLF1, early genes BARF1 and BHRF1, late genes BcLF1and BLLF1) in EBVaGCs.RESULTS: Eleven EBV positive samples existed in gastric carcinoma tissues (6.39%). No EBV positive sample was found in corresponding para-carcinoma tissues. The difference between EBV positivity in carcinoma tissues and corresponding para-carcinoma tissues was significant(x2 = 9.0909, P = 0.0026). Transcripts of Qp and EBNA1were detected in all the 11 EBVaGCs, while both Wp and Cp were silent. EBNA2, LMP1 and LMP2B mRNA were absent in all the cases, while LMP2A mRNA was detected in 4 of the 11 cases. Of the 11 EBVaGCs, 7 exhibited BcLF1 transcripts and 2 exhibited BHRF1 transcripts. The transcripts of BZLF1and BARF1 were detected in 5 cases, respectively. No BLLF1and BRLF mRNA were detected.CONCLUSION: The latent pattern of EBV in gastric carcinoma corresponds to the latency Ⅰ/Ⅱ. Some lyric infection genes are expressed in EBVaGCs tissues. BARF1 and BHRF1genes may play an important role in tumorigenesis of gastric carcinoma.

Epstein-Barr virus and Burkitt lymphoma

In 1964,a new herpesvirus,Epstein-Barr virus(EBV),was discovered in cultured tumor cells derived from a Burkitt lymphoma(BL)biopsy taken from an African patient.This was a momentous event that reinvigorated research into viruses as a possible cause of human cancers.Subsequent studies demonstrated that EBV was a potent growth-transforming agent for primary B cells,and that all cases of BL carried characteristic chromosomal translocations resulting in constitutive activation of the c-MYC oncogene.These results hinted at simple oncogenic mechanisms that would make Burkitt lymphoma paradigmatic for cancers with viral etiology.In reality,the pathogenesis of this tumor is rather complicated with regard to both the contribution of the virus and the involvement of cellular oncogenes.Here,we review the current understanding of the roles of EBV and c-MYC in the pathogenesis of BL and the implications for new therapeutic strategies to treat this lymphoma.

Plasma Epstein-Barr virus DNA as a biomarker for nasopharyngeal carcinoma

Nasopharyngeal carcinoma(NPC)is common in southern China and Southeast Asia.Epstein-Barr virus(EBV)infection is an important etiology for NPC,and EBV genome can be detected in almost all tumor tissues of NPC in this region.Plasma EBV DNA,when quantitatively analyzed using real-time polymerase chain reaction(PCR),has been developed as a biomarker for NPC.In this review,the different clinical applications of plasma EBV DNA in the management of NPC,including screening,monitoring,and prognostication,are discussed.In addition,the biological issues of circulating EBV DNA,including the molecular nature and clearance kinetics,are also explored.

Epstein-Barr virus:Silent companion or causative agent of chronic liver disease?

The Epstein-Barr virus(EBV)has an important and multifaceted role in liver pathology.As a member of the herpes virus family,EBV establishes a persistent infection in more than 90%of adults.Besides acute hepatitis during primary infection,many clinical syndromes of interest for the hepatologist are associated with EBV infection.The role of EBV in the evolution of chronic hepatitis from hepatotropic viruses is considered.Chronic EBVassociated hepatitis is suspected in immunocompetent adults with compatible serology,suggestive histology and detection of the viral genome in the liver and/or increase of specific circulating cytotoxic T-lymphocytes.EBV is the main cause of post-transplant lymphoproliferative disorders which occur in up to 30%of cases.EBV-driven lymphoproliferative diseases are also recognized in non-immunocompromised patients and liver is involved in up to a third of the cases.Directly implicated in the pathogenesis of different tumors,EBV has a disputable role in hepatocellular carcinoma carcinogenesis.Further research is required in order to establish or reject the role of EBV in human liver cancer.This paper attempts to discuss the range of EBV-associated chronic liver diseases in immunocompetent patients,from mild,self-limiting mononuclear hepatitis to liver cancer.

The interplay of host genetic factors and Epstein-Barr virus in the development of nasopharyngeal carcinoma

The interplay between host cell genetics and Epstein-Barr virus(EBV) infection contributes to the development of nasopharyngeal carcinoma(NPC). Understanding the host genetic and epigenetic alterations and the influence of EBV on cell signaling and host gene regulation will aid in understanding the molecular pathogenesis of NPC and provide useful biomarkers and targets for diagnosis and therapy. In this review, we provide an update of the oncogenes and tumor suppressor genes associated with NPC, as well as genes associated with NPC risk including those involved in carcinogen detoxification and DNA repair. We also describe the importance of host genetics that govern the human leukocyte antigen(HLA) complex and immune responses, and we describe the impact of EBV infection on host cell signaling changes and epigenetic regulation of gene expression. High-power genomic sequencing approaches are needed to elucidate the genetic basis for inherited susceptibility to NPC and to identify the genes and pathways driving its molecular pathogenesis.

DNA methylation in gastric cancer, related to Helicobacter pylori and Epstein-Barr virus

Gastric cancer is a leading cause of cancer death worldwide,and significant effort has been focused on clarifying the pathology of gastric cancer.In particular,the development of genome-wide analysis tools has enabled the detection of genetic and epigenetic alterations in gastric cancer;for example,aberrant DNA methylation in gene promoter regions is thought to play a crucial role in gastric carcinogenesis.The etiological viewpoint is also essential for the study of gastric cancers,and two distinct pathogens,Helicobacter pylori(H.pylori)and Epstein-Barr virus(EBV),are known to participate in gastric carcinogenesis.Chronic inflammation of the gastric epithelium due to H.pylori infection induces aberrant polyclonal methylation that may lead to an increased risk of gastric cancer.In addition,EBV infection is known to cause extensive methylation,and EBV-positive gastric cancers display a high methylation epigenotype,in which aberrant methylation extends to not only Polycomb repressive complex(PRC)-target genes in embryonic stem cells but also non-PRC-target genes.Here,we review aberrant DNA methylation in gastric cancer and the association between methylation and infection with H.pylori and EBV.

Epstein-Barr virus infection and persistence in nasopharyngeal epithelial cells

Epstein-Barr virus(EBV) infection is closely associated with undifferentiated nasopharyngeal carcinoma(NPC), strongly implicating a role for EBV in NPC pathogenesis; conversely, EBV infection is rarely detected in normal nasopharyngeal epithelial tissues. In general, EBV does not show a strong tropism for infecting human epithelial cells, and EBV infection in oropharyngeal epithelial cells is believed to be lytic in nature. To establish life-long infection in humans, EBV has evolved efficient strategies to infect B cells and hijack their cellular machinery for latent infection. Lytic EBV infection in oropharyngeal epithelial cells, though an infrequent event, is believed to be a major source of infectious EBV particles for salivary transmission. The biological events associated with nasopharyngeal epithelial cells are only beginning to be understood with the advancement of EBV infection methods and the availability of nasopharyngeal epithelial cell models for EBV infection studies. EBV infection in human epithelial cells is a highly inefficient process compared to that in B cells, which express the complement receptor type 2(CR2) to mediate EBV infection. Although receptor(s) on the epithelial cell surface for EBV infection remain(s) to be identified, EBV infection in epithelial cells could be achieved via the interaction of glycoproteins on the viral envelope with surface integrins on epithelial cells, which might trigger membrane fusion to internalize EBV in cells. Normal nasopharyngeal epithelial cells are not permissive for latent EBV infection, and EBV infection in normal nasopharyngeal epithelial cells usually results in growth arrest. However, genetic alterations in premalignant nasopharyngeal epithelial cells, including p16 deletion and cyclin D1 overexpression, could override the growth inhibitory effect of EBV infection to support stable and latent EBV infection in nasopharyngeal epithelial cells. The EBV episome in NPC is clonal in nature, suggesting that NPC develops from a single EBV-infected nasopharyngeal epithelial cell, and the establishment of persistent and latent EBV infection in premalignant nasopharyngeal epithelium may represent an early and critical event for NPC development.

Chronic Epstein-Barr virus-related hepatitis in immunocompetent patients

AIM: To investigate reactivated Epstein-Barr virus (EBV) infection as a cause for chronic hepatitis. METHODS: Patients with occasionally established elevated serum aminotransferases were studied. HIV, HBV and HCV-infections were excluded as well as any other immunosuppressive factors, metabolic or toxic disorders. EBV viral capsid antigen (VCA) IgG and IgM, EA-R and EA-D IgG and Epstein-Barr nuclear antigen (EBNA) were measured using IFA kits. Immunophenotyping of whole blood was performed by multicolor flow cytometry. CD8+ T cell responses to EBV and PHA were determined according to the intracellular expression of IFN-γ. RESULTS: The mean alanine aminotransferase (ALT) and gamma glutamyl transpeptidase (GGTP) values exceeded twice the upper normal limit, AST/ALT ratio < 1. Serology tests showed reactivated EBV infection in all patients. Absolute number and percentages of T, B and NK cells were within the reference ranges. Fine subset analysis, in comparison to EBV+ healthy carriers, revealed a significant decrease of naive T cells (P < 0.001), accompanied by increased percentage of CD45RA- (P < 0.0001), and terminally differentiated CD28-CD27- CD8+ T cells (P < 0.01). Moderately elevated numbers of CD38 molecules on CD8+ T cells (P < 0.05) proposed a low viral burden. A significantly increased percentage of CD8+ T cells expressing IFN-γ in response to EBV and PHA stimulation was registered in patients, as compared to controls (P < 0.05). Liver biopsy specimens from 5 patients revealed nonspecific features of low-grade hepatitis.CONCLUSION: Chronic hepatitis might be a manifestation of chronic EBV infection in the lack of detectable immune deficiency; the expansion of CD28- CD27- and increase of functional EBV-specific CD8+ T cells being the only surrogate markers of viral activity.

Serological diagnosis of Epstein-Barr virus infection: Problems and solutions

Serological tests for antibodies specific for Epstein-Barr virus(EBV) antigens are frequently used to define infection status and for the differential diagnosis of other pathogens responsible for mononucleosis syndrome. Using only three parameters [viral capsid antigen(VCA) Ig G, VCA Ig M and EBV nuclear antigen(EBNA)-1 Ig G],it is normally possible to distinguish acute from past infection: the presence of VCA Ig M and VCA Ig G without EBNA-1 Ig G indicates acute infection, whereas the presence of VCA Ig G and EBNA-1 Ig G without VCA Ig M is typical of past infection. However, serological findings may sometimes be difficult to interpret as VCA Ig G can be present without VCA Ig M or EBNA-1 Ig G in cases of acute or past infection, or all the three parameters may be detected simultaneously in the case of recent infection or during the course of reactivation. A profile of isolated EBNA-1 Ig G may also create some doubts. In order to interpret these patterns correctly, it is necessary to determine Ig G avidity, identify anti-EBV Ig G and Ig M antibodies by immunoblotting, and look for heterophile antibodies, anti-EA(D) antibodies or viral genome using molecular biology methods. These tests make it possible to define the status of the infection and solve any problems that may arise in routine laboratory practice.

Polymorphisms of Epstein-Barr virus BHRF1 gene, a homologue of bcl-2

Background and Objective: EBV BamHI fragment H rightward open reading frame 1 (BHRF1), the Epstein-Barr virus (EBV) early gene, is structurally and functionally homologous to the oncogene bcl-2 and may play an important role in the development of EBV-associated tumors. To characterize the polymorphisms of BHRF1 in EBV-associated tumors, we analyzed the sequences of BHRF1 in isolates from nasopharyngeal carcinoma (NPC) and EBV-associated gastric carcinoma (EBVaGC) biopsies as well as throat washing (TW) samples from healthy donors. Methods: BHRF1 DNA sequences were analyzed by polymerase chain reaction (PCR) and sequencing for 39 NPC samples, 40 EBVaGC samples, and 53 EBV-positive TW samples from healthy donors. The variants of BHRF1 gene were classified according to the signature changes. The EBV types 1 and 2 at nuclear antigen (EBNA) 3C locus were determined by PCR. Results: Compared with EBV standard cell line B95-8, all isolates carried a silent mutation at amino acid (AA) 80 (nucleotide 54616 T→C), the AA88 L→V mutation was found in most isolates, and the AA79 V→L mutation in a few isolates. Other mutations were sporadically distributed. Based on the mutations at AA88 and AA79, 3 distinct variants of BHRF1 genes, designated as 79V88V, 79L88L, and 79V88L, were identified. The 79V88V was the most common variant. The distribution of the BHRF1 variants among the NPC, EBVaGC, and TW samples was not significant. The corresponding regions of bcl-2 homologues were conserved in all isolates except for 3 samples. The distribution of BHRF1 variants in type 1 and type 2 strains was significant different (P < 0.001, contingency coefficient was 0.554). Conclusions: The 79V88V is the dominant variant in NPC, EBVaGC, and TW samples from healthy donors and preferential linkages between BHRF1 and EBNA3C variants exist. Conserved BHRF1 in Bcl-2 homologous domains is helpful to remain the important role of BHRF1.

H pylori (CagA) and Epstein-Barr virus infection in gastric carcinomas:Correlation with p53 mutation and c-Myc,Bcl-2 and Bax expression

AIM: To investigate the interrelationship between H pylori and Epstein-Barr virus (EBV) infection in the gastric carcinogenesis having in focus the p53 mutation and the c-Myc, Bcl-2 and Bax expression. METHODS: seventy-one gastric carcinoma tissues were assessed by polymerase chain reaction (PCR) for H pylori and in situ hybridization for EBV. c-Myc, Bcl-2 and Bax expression were detected by immunohistochemistry and single-stranded conformational polymorphism (SSCP) for p53 mutation. RESULTS: The positivity rates for H pylori and EBV were 94.4% and 8.45%, respectively. The majority of the cases displayed only the H pylori presence. All EBV positive cases were also H pylori positive. None infectious agent was observed in 5.55% of the cases. The intestinal type tumor was more frequent in the co-infected and non-infected groups. The female predominated in the non-infected group showing statistical significance (70.4% vs 29.6%, P=0.039). The Bcl-2 was only detected in the group exclusively infected by H pylori. However, c-Myc and Bax were detected in the three groups but with a low frequency in the co-infected group. Mutation of p53 was present in all groups, with the highest frequencies in the H pylori positive groups. CONCLUSION: The frequency of H pylori infection in gastric carcinomas was high. The presented data indicated that gastric carcinogenesis has different pathways depending of the presence of the two investigated infectious agents, suggesting a possible involvement of H pylori with apoptotic process. The low expression of c-Myc and Bax in the EBV-positive groups suggests that EBV may inhibit the expression of these proteins. Nevertheless, p53 mutation shows to be a relevant alteration, independent of both infectious agents.

Correlation of Epstein-Barr virus and its encoded proteins with Helicobacter pylori and expression of c-met and c-myc in gastric carcinoma

瞄准：为了调查 Epstein-Barr 病毒(EBV ) 和 EBV- 的相互关系，并且在胃的致癌作用探索他们的角色，与 Helicobacter pylori (H pylori ) 编码了蛋白质感染和表示遇见 c 并且在胃的癌的 c-myc oncogene 蛋白质。方法：185 胃的癌纸巾被聚合酶链反应(PCR ) 检测为 EBV 染色体的南部的污点和为编码 EBV 的小 RNA 1 (EBER1 ) 的原位杂交(ISH ) 。有积极 EBER1 信号的胃的癌被证实联系 EBV 的胃的癌(EBVaGC ) 。在 185 胃的癌的 H pylori 感染的地位被快速的 urease 和 PCR 估计。有积极 PCR 和 urease 的样品被定义为 H pylori 感染。表示遇见 c 并且在 EBVaGC 和匹配的 EBV 否定的胃的癌(EBVnGC ) 的纸巾的 c-myc oncogene 蛋白质被免疫组织化学检验。RT-PCR 和南部的杂交被用来检测原子抗原(EBNA ) 的表示 1 和 2，潜伏的膜蛋白质(LMP ) 1，在 EBVaGC 情况中的早基因 BARF1 和 BHRF1。结果：在 185 胃的癌的 H pylori 和 EBV 的积极的率是 59.45%(110/185 ) 并且 7.03%(13/185 ) 分别地。没有差别在在 pylori 积极的 H 和 H 之间的性别，年龄，病理学的区别，临床的阶段和淋巴节点转移被发现 pylori 否定的胃的癌。然而，在窦的 H pylori 感染的积极的率胃的癌比贲门和身体的高胃的癌。在我们的系列，年龄，病理学的区别，临床的阶段，淋巴节点转移和癌症的地点不在 EBVnGC 和 EBVaGC 之间是不同的，当在男病人的 EBV 的积极的率比女病人的显著地高时。在联系 EBV 、 EBV 否定的胃的癌的 H pylori 的确实是 46.15%(6/13 ) 并且 81.40%(104/172 ) 分别地。在 EBV 和 H pylori 感染之间没有重要关联。在表示上遇见 c 比在 EBVnGC 组在 EBVaGC 组是显著地更高的。然而，遇见 c 并且 c-myc 表示没显示出在二个组之间的有效差量。EBNA1 的抄本在所有 13 EBVaGCs 被检测，当 EBNA2 和 LMP1 mRNA 没被检测时。13 个盒子中的六个展出了 BARF1 抄本和 2 个展出 BHRF1 抄本。结论：在 EBVnGCs 的 H pylori 的确实比 EBVaGCs 的高，但是没有重要关联在 EBV 感染和 H pylori 感染之间被发现。H pylori 积极的胃的癌在窦地点是占优势的，当 EBVaGC 在贲门 / 身体地点有优势的一个趋势时。EBV 感染在 EBVaGC 与遇见 c 的反常表示然而并非与 c-myc 蛋白质被联系。在表示上遇见 c 没被 LMP1 导致。BARF1 和 BHRF1 可以通过不同小径在 EBVaGC 的肿瘤发生起重要作用。