The Impact of Epstein Bar Virus On Hodgkin Lymphoma's Histopathological Patterns in Morocco

Abstract Abstract 4781 Background: In Morocco, improvement of living conditions and access to healthcare has increased life expectancy from 58 years in 1980 to 72 years in 2010. There has been a corresponding decrease in early childhood infections, including Epstein Barr virus (EBV) infection, which is associated with Hodgkin lymphoma (HL). Mixed cellularity (MC) was the most common histopathological subset of HL in Morocco. Prior studies have shown the shift to nodular sclerosis (NS) subset since 1998. Currently, the incidence of NS subtype is still predominant in our country. Our aim is to study the incidence of EBV infection in HL Moroccan population and correlate its decrease to explain the shift of HL histopathological pattern. Patients and methods: We compared children and adults with HL diagnosed during 3 periods: 1980–1995, 1998–2005 and 2010–2011 in the same university medical centre. All histological samples were prepared for examination by paraffin method, than stained by Hematoxylin staining protocol. Immunuhistochemical features of Hodgkin Reed Sternberg cells were performed to assess the expression of antibodies markers (CD30, CD15). The EBV profiling was identified by immunohistochemical stains for EBV latent membrane protein 1 (LMP-1) for the last periods. Statistical comparison of all the features was performed by Epi Info software. Results: The features of 1200 HL patients were enrolled. The average number of HL cases per year was 46 patients for the first period versus 74 patients for the last period. The mean age was respectively 24 years (range 2–64 years) for the first period, 32 years (range 2–60 years) for the second period and 34 years (range 3–76 years) for the third one. Sex-Ratio showed male predominance. The comparison of HL incidence through the age over the past 30 years is further characterized by a significant higher incidence in elderly patients (2% versus 10%), and lower incidence in young children (32% versus 7%). The expression of LMP1 in HRS is significantly reduced between the two last periods (P=0.001). LMP1 positivity is higher in patients under fifteen years than in young adults. Currently, NS is the most prevalent histological subtype with a significant increasing frequency through the three periods (p< 0.001) instead of MC subtype. (Table1). Conclusion: HL pattern in Morocco tends to be like in developed countries. The shift of HL histological subtype from CM to NS could be explained by the decrease of EBV infection in Hodgkin Reed Sternberg cells. More patients need to be enrolled to confirm this hypothesis Disclosures: No relevant conflicts of interest to declare.

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The Impact of Latent Epstein-Barr Virus Infection on Outcome in Children and Adolescents with Hodgkin’s Lymphoma.

Blood ◽

10.1182/blood.v104.11.3121.3121 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3121-3121

Author(s):

Alexander Claviez ◽

Markus Tiemann ◽

Heike Lueders ◽

Reza Parwaresch ◽

Guenther Schellong ◽

...

Keyword(s):

Overall Survival ◽

Children And Adolescents ◽

Hodgkin’S Lymphoma ◽

Epstein Barr Virus ◽

Hodgkin's Lymphoma ◽

Barr Virus ◽

Ebv Infection ◽

Nodular Sclerosis ◽

Epstein Barr ◽

The Impact

Abstract The prognostic significance of latent Epstein-Barr virus (EBV) infection in Hodgkin’s lymphoma (HL) is debated controversially. Especially in the pediatric age group, no conclusive data are available due to small series. 842 children and adolescents (55% male) with a median age of 13.7 years (range, 2–20) from consecutive pediatric DAL/GPOH multicenter treatment studies HD-90 and HD-95 were studied for the presence of latent EBV infection in Hodgkin and Reed-Sternberg cells by immunostaining against latent membrane protein 1 (LMP-1). Histology subtypes were as follows: nodular sclerosis (NSHL) 549, mixed cellularity (MCHL) 190, lymphocyte predominance (NLPHL) 90, lymphocyte depletion (LDHL) 6, lymphocyte-rich classical HL (LRCHL) 5, not specified 2. 88 patients had stage I, 470 had stage II, 172 had stage III and 112 had stage IV. B symptoms were present in 274 patients (33%). LMP status was compared with clinical parameters and established risk factors. A total of 263 patients (32%) were LMP positive. EBV infection correlated with gender (male 39% vs. female 23%; p<.001), histological subtype (MCHL 69% vs. NSHL 22% vs. NLPHL 6%; p<.001) and age (<10 years 67% vs ≥10 years 28%, p<.001. With a median follow-up of 4.9 years (0.3–12) 820 patients (97%) are alive. Probability of overall survival at 10 years (±SD) for EBV negative and positive patients was 98±1% and 95±1%, respectively (p=.017 by log-rank test). Probability of failure-free survival (FFS) in LMP positive and negative patients was 89±2% and 84±4%, respectively (p=.86). With respect to LMP status, a negative effect of latent EBV infection on overall survival became evident only for patients treated for advanced stages (p=.003), those with nodular sclerosis subtype Bennett II (p=.02) and B symptoms (p=.05). In a multivariate regression analysis, allocation to treatment group (RR=3.7) and LMP positivity (RR=3.01) were independent factors for overall survival and presence of B symptoms (RR=2.4) for FFS. Under current highly effective polychemotherapy with or without involved field radiotherapy in pediatric HL, latent EBV infection has no influence on FFS in univariate and multivariate analysis. LMP positivity, however, seems to be associated with an inferior overall survival in some subgroups.

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Modulation of alternative splicing during early infection of human primary B lymphocytes with Epstein-Barr virus (EBV): a novel function for the viral EBNA-LP protein

Nucleic Acids Research ◽

10.1093/nar/gkab787 ◽

2021 ◽

Vol 49 (18) ◽

pp. 10657-10676

Author(s):

Evelyne Manet ◽

Hélène Polvèche ◽

Fabrice Mure ◽

Paulina Mrozek-Gorska ◽

Florian Roisné-Hamelin ◽

...

Keyword(s):

Alternative Splicing ◽

B Lymphocytes ◽

Splice Variant ◽

Epstein Barr Virus ◽

Human Herpesvirus ◽

Splicing Regulation ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr ◽

The Impact

Abstract Epstein-Barr virus (EBV) is a human herpesvirus associated with human cancers worldwide. Ex vivo, the virus efficiently infects resting human B lymphocytes and induces their continuous proliferation. This process is accompanied by a global reprogramming of cellular gene transcription. However, very little is known on the impact of EBV infection on the regulation of alternative splicing, a pivotal mechanism that plays an essential role in cell fate determination and is often deregulated in cancer. In this study, we have developed a systematic time-resolved analysis of cellular mRNA splice variant expression during EBV infection of resting B lymphocytes. Our results reveal that major modifications of alternative splice variant expression appear as early as day 1 post-infection and suggest that splicing regulation provides—besides transcription—an additional mechanism of gene expression regulation at the onset of B cell activation and proliferation. We also report a role for the viral proteins, EBNA2 and EBNA-LP, in the modulation of specific alternative splicing events and reveal a previously unknown function for EBNA-LP—together with the RBM4 splicing factor—in the alternative splicing regulation of two important modulators of cell proliferation and apoptosis respectively, NUMB and BCL-X.

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The influence of human genetic variation on Epstein–Barr virus sequence diversity

Scientific Reports ◽

10.1038/s41598-021-84070-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sina Rüeger ◽

◽

Christian Hammer ◽

Alexis Loetscher ◽

Paul J. McLaren ◽

...

Keyword(s):

Genetic Variation ◽

Epstein Barr Virus ◽

Rare Variants ◽

Amino Acid Level ◽

Genomic Variation ◽

Human Genetic Variation ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr ◽

The Impact

AbstractEpstein–Barr virus (EBV) is one of the most common viruses latently infecting humans. Little is known about the impact of human genetic variation on the large inter-individual differences observed in response to EBV infection. To search for a potential imprint of host genomic variation on the EBV sequence, we jointly analyzed paired viral and human genomic data from 268 HIV-coinfected individuals with CD4 + T cell count < 200/mm3 and elevated EBV viremia. We hypothesized that the reactivated virus circulating in these patients could carry sequence variants acquired during primary EBV infection, thereby providing a snapshot of early adaptation to the pressure exerted on EBV by the individual immune response. We searched for associations between host and pathogen genetic variants, taking into account human and EBV population structure. Our analyses revealed significant associations between human and EBV sequence variation. Three polymorphic regions in the human genome were found to be associated with EBV variation: one at the amino acid level (BRLF1:p.Lys316Glu); and two at the gene level (burden testing of rare variants in BALF5 and BBRF1). Our findings confirm that jointly analyzing host and pathogen genomes can identify sites of genomic interactions, which could help dissect pathogenic mechanisms and suggest new therapeutic avenues.

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Autoimmune and lymphoproliferative malignant diseases associated with Epstein-Barr viral infection

Pediatrician (St Petersburg) ◽

10.17816/ped10489-96 ◽

2019 ◽

Vol 10 (4) ◽

pp. 89-96

Author(s):

Anna V. Fedorova ◽

Vladimir N. Timchenko ◽

Svetlana L. Bannova ◽

Tatyana A. Kaplina ◽

Alexey L. Balashov ◽

...

Keyword(s):

Lupus Erythematosus ◽

Current Data ◽

Barr Virus ◽

Ebv Infection ◽

The Past ◽

Oncological Diseases ◽

Autoimmune Processes ◽

Epstein Barr ◽

Cellular And Humoral Immunity ◽

The Impact

Currently, in medical practice, there is a high interest in diseases caused by herpes viruses, among them the Epstein-Barr virus (EBV) occupies the leading place. Almost 90% of the worlds population over the age of 40 are infected with VEB. In patients of the first two years, the proportion of asymptomatic carriage reaches 90%, and at the age of 2-10 30-50%. The article considers current data on the impact of EBV on cellular and humoral immunity, its connection with autoimmune and lymphoproliferative diseases. EBV has been shown to play a significant role in the onset of oncological diseases such as Hodgkins lymphoma, Burkitts lymphoma, nasopharyngeal carcinomas, as well as autoimmune diseases systemic lupus erythematosus, rheumatoid arthritis, Sjogrenʼs syndrome, autoimmune hepatitis, lymphoid interstitial hepatitis, lymphoid interstitial syndrome. The results of studies over the past 5 years of cases of activation of autoimmune processes associated with EBV infection, as well as predisposing factors underlying these manifestations, are presented. Due to the fact that the autoimmune effect of EBV infection is manifested in various organs and tissues, this problem is multidisciplinary, affecting such fields of medicine as pediatrics, infectious diseases, endocrinology, oncology, gynecology, ophthalmology, gastroenterology, etc.

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The influence of human genetic variation on Epstein-Barr virus sequence diversity

10.1101/2020.12.02.20242370 ◽

2020 ◽

Author(s):

Sina Rüeger ◽

Christian Hammer ◽

Alexis Loetscher ◽

Paul J McLaren ◽

Dylan Lawless ◽

...

Keyword(s):

Genetic Variation ◽

Epstein Barr Virus ◽

Rare Variants ◽

Amino Acid Level ◽

Genomic Variation ◽

Human Genetic Variation ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr ◽

The Impact

AbstractEpstein-Barr virus (EBV) is one of the most common viruses latently infecting humans. Little is known about the impact of human genetic variation on the large inter-individual differences observed in response to EBV infection. To search for a potential imprint of host genomic variation on the EBV sequence, we jointly analyzed paired viral and human genomic data from 268 HIV-coinfected individuals with CD4+ T cell count <200/mm3 and elevated EBV viremia. We hypothesized that the reactivated virus circulating in these patients could carry sequence variants acquired during primary EBV infection, thereby providing a snapshot of early adaptation to the pressure exerted on EBV by the individual immune response. We searched for associations between host and pathogen genetic variants, taking into account human and EBV population structure. Our analyses revealed significant associations between human and EBV sequence variation. Three polymorphic regions in the human genome were found to be associated with EBV variation: one at the amino acid level (BRLF1:p.Lys316Glu); and two at the gene level (burden testing of rare variants in BALF5 and BBRF1). Our findings confirm that jointly analyzing host and pathogen genomes can identify sites of genomic interactions, which could help dissect pathogenic mechanisms and suggest new therapeutic avenues.

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Impact Of Treatment On Regulatory CD4+ T Lymphocytes, TH17 and Cytokines In Patients With Classical Hodgkin’s Lymphoma

Blood ◽

10.1182/blood.v122.21.1756.1756 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1756-1756

Author(s):

Adriana M. Damasco Penna ◽

Priscilla Brito Silva ◽

Joyce M. K. Silva ◽

Maria Mirtes Sales ◽

Elma Maria Chaves ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Conflicts Of Interest ◽

Treatment Strategies ◽

Interleukin 17 ◽

Barr Virus ◽

Epstein Barr ◽

The Impact

Abstract Introduction Although immunosuppression has long been recognized in classical Hodgkin lymphoma (cHL), the underlying basis for the lack of an effective immune response against the tumor remains unclear. Increased frequencies of regulatory CD4+ T lymphocytes in the tumor microenvironment and peripheral blood have been proposed as one of the mechanisms for this anergic state. However, little is known about the disbalance between regulatory and effector CD4+ subpopulations and cytokines in the peripheral blood of cHL patients and how treatment can modify this regulatory/effector ratio. In this study, we analyzed the regulatory and effector CD4+ subpopulations together with pro and anti-inflammatory cytokines in peripheral blood of cHL patients and the impact of treatment on these cells and cytokines. Material and Methods This is an open multicenter study and, so far, we included 54 patients from December 2009 to July 2013. Thirty-four patients have completed therapy on July 2012 and were included in this study. Blood was drawn at diagnosis and after completion of treatment (1 to 4 months). Nineteen healthy blood donors volunteers were recruited as controls. Quantification of regulatory and effector T lymphocytes was done by flow cytometry using CD3, CD8, CD4, CD25, Foxp3, CTLA4, GITR and interleukin-17 (IL17) antibodies. Ten cytokines were studied: IL-2, IL-4, IL-5, IL-6, IL-10, IL-17A, sIL-2Rα, TNF-α, IFN-γ, and VEGF. Cytokine levels were determined by multiplexed immunoassay system. All these parameters were correlated to phenotypic and clinical parameters in uni- and multivariate models pre and post-treatment. In this study, only cHL patients whose histology could be confirmed and EBV association established were studied. All patients were HIV negative and received ABVD chemotherapy protocol and radiotherapy if necessary. Results From the 34 cHL patients recruited for this study, 17 (50%) were male, 16 (47%) had Epstein-Barr virus (EBV) related cHL, 27 (79%) patients presented with B symptoms and 18 (53%) patients had advanced diseases at diagnosis. Results of subsets of CD4+ T cells and cytokines are summarized in the following table: After treatment, the percentage of regulatory CD4+CD25highFoxP3+ and effector CD4+IL17+ T lymphocytes were not different from diagnosis (0.9 vs 0.4, p=0.45; 0.6 vs 0.9, p=0.52; respectively) and from controls (0.9 vs 0.3, p=0.22; 0.6 vs 0.7, p=0.84; respectively). Interestingly, increased CD4+CD25highFoxP3+ T lymphocytes were correlated with advanced disease at diagnosis (p=0.03) and an erythrocyte sedimentation rate (ESR) > 30 mmHg (p=0.01). Additionally, we found a negative correlation between soluble IL-2Rα and CD4+GITR+ (p=0.02) and CD4+FOXP3+ (p=0.02). Conclusions In this study, we showed that, after treatment, there was a decrease of some subsets of CD4+ T cells with regulatory phenotype, together with a decrease of IL-6, IL-10 and sIL-2Rα. Understanding cHL associated immunosuppression and the immune reconstitution after treatment maybe the key to develop new treatment strategies, designed to manipulate regulatory activity. Further studies investigating these CD4+ T lymphocytes subpopulations with functional assays are warranted. Given that the incidence of EBV-related cHL, disease presentation and severity are different in developing countries than in developed ones, we emphasize the importance of this ongoing Brazilian multicenter project. Disclosures: No relevant conflicts of interest to declare.

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A novel comparison of Epstein-Barr virus with broad histological spectrum of oral squamous cell carcinoma

Pakistan Journal of Medical Sciences ◽

10.12669/pjms.35.5.899 ◽

2019 ◽

Vol 35 (5) ◽

Author(s):

Muhammad Wasif Saleem ◽

Faraz Ahmed Baig ◽

Naila Irum Hadi

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Buccal Mucosa ◽

Epstein Barr Virus ◽

Histological Subtype ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr

Objectives: To evaluate the immunohistochemical expression of Epstein-Barr virus (EBV) in broad spectrum histological subtypes of oral squamous cell carcinoma (OSCC) and to determine the relationship of EBV with clinicopathological parameters of OSCC. Methods: This cross-sectional study included 150 clinically diagnosed OSCC cases from the outpatient of Ziauddin University Hospital from March, 2017 to October, 2018. These were confirmed on histological examination and categorized into conventional squamous cell carcinoma (SCC) and rare variants. Conventional SCC was subcategorized into keratinizing (KSCC), non-keratinizing (NKSCC), and hybrid SCC (HSCC). EBV status was compared among various histological tumor entities and clinicopathological characteristics of OSCC using immunohistochemistry. Chi-square test was used to determine the association of each histological subtype with EBV status with P-value <0.05 considered as statistically significant. Results: Conventional tumor was the most frequent squamous cell carcinoma (n=126; 84%). A significant statistical link of EBV infection was observed with rare histological tumors exhibiting acantholysis (P=0.01), as well as tumors involving buccal mucosa (P=0.03), and habitual smokers (P=0.001). Conclusions: In this study, acantholytic tumor, a rare histological subtype of OSCC, tended to be EBV related. Moreover, OSCC cases bearing EBV infection were more likely smokers favoring buccal mucosa as primary anatomical site for oral cancer. doi: https://doi.org/10.12669/pjms.35.5.899 How to cite this:Saleem MW, Baig FA, Hadi NI. A novel comparison of Epstein-Barr virus with broad histological spectrum of oral squamous cell carcinoma. Pak J Med Sci. 2019;35(5):---------. doi: https://doi.org/10.12669/pjms.35.5.899 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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The Impact of Epstein-Barr Virus Infection on Juvenile Idiopathic Arthritis Activity and Patient’s Response to Treatment

Journal of Clinical Medicine ◽

10.3390/jcm9113453 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3453

Author(s):

Violetta Opoka-Winiarska ◽

Ewelina Grywalska ◽

Aleksandra Sobiesiak ◽

Jacek Roliński

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Disease Activity ◽

Epstein Barr Virus ◽

Response To Treatment ◽

Barr Virus ◽

Ebv Infection ◽

History Of ◽

Epstein Barr ◽

The Impact ◽

Infection Markers

This study aimed to investigate the relationship between Epstein-Barr virus (EBV) infection and the onset of juvenile idiopathic arthritis (JIA), disease activity, and response to treatment. The study included 44 children with JIA, 23 children with different types of arthritis, and 44 controls. We measured EBV infection markers, including the EBV DNA load and the concentration of antibodies to viral antigens, at disease onset, before treatment. Six months after JIA diagnosis and the initiation of treatment patients with anti-viral capsid antigen IgG had a higher disease activity and worse response to treatment than patients without previous infection. After six months of treatment, the probability of disease inactivity in children without a history of EBV infection was almost 6.5 times greater than in a child with a history of infection. Furthermore, the probability of a better response after six months of treatment in a child with a history of EBV infection was more than five times smaller than in a child without infection. A past EBV infection can have a negative effect on achieving disease remission and may be associated with a worse response to treatment. Our results do not indicate the need for routine assessment of EBV infection markers in patients with JIA.

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