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Objectives: To assess the incidences of Herpes Simplex-1 and 2 (HSV-1, HSV-2), Cytomegalovirus (CMV), Epstein–Barr Virus (EBV) reactivations in critically ill COVID-19 patients. To determine the association between viral reactivation and in-hospital mortality, Intensive Care Unit Bloodstream infection (ICU–BSI), ventilator-associated pneumonia (VAP). Design: Observational retrospective cohort study. Setting: COVID-19 Intensive Care Unit. Patients: From November 2020 to May 2021, one hundred and twenty patients with COVID-19 severe pneumonia were enrolled and tested for HSV-1, HSV-2, CMV and EBV at the admission in ICU and weekly until discharge or death. The presence of VAP and ICU–BSI was evaluated according to clinical judgement and specific diagnostic criteria. Measurements and main results: One hundred and twenty patients were enrolled. Multiple reactivations occurred in 75/120 (63%) patients, single reactivation in 27/120 patients (23%). The most reactivated Herpesvirus was EBV, found in 78/120 (65%) patients. The multivariate analysis demonstrated that viral reactivation is a strong independent risk factor for in-hospital mortality (OR = 2.46, 95% CI 1.02–5.89), ICU–BSI (OR = 2.37, 95% CI 1.06–5.29) and VAP (OR = 2.64, 95% CI 1.20–5.82). Conclusions: Human Herpesviruses reactivations in critically ill patients with COVID-19 severe Pneumonia are associated with mortality and with a higher risk to develop both VAP and ICU–BSI. Key points: Question: The impact of Human Herpesviruses reactivations on the morbidity and mortality of COVID-19 critically ill patients is controversial. Findings: Critically ill patients with COVID-19 are at high risk for both EBV, HSV and CMV reactivations. Meanings: Further large prospective studies will be necessary to clarify if the presence of active viral replication must be considered causal agent affecting mortality or the indirect manifestation of immune paralysis in the worst patients. [ABSTRACT FROM AUTHOR]

Simultaneous multi-target detection and multi-site gene editing are two key factors restricting the development of disease diagnostic and treatment technologies. Despite numerous explorations on the source, classification, functional features, crystal structure, applications and engineering of CRISPR-Cas13a, all reports use the contiguous target RNA activation paradigm that only enables single-target detection in vitro and one-site gene editing in vivo. Here we propose a noncontiguous target RNA activation paradigm of Cas13a and establish a CRISPR-Cas13a Gemini System composed of two Cas13a:crRNA binary complexes, which can provide rapid, simultaneous, highly specific and sensitive detection of two RNAs in a single readout, as well as parallel dual transgene knockdown. CRISPR-Cas13a Gemini System are demonstrated in the detection of two miRNAs (miR-155 and miR-375) for breast cancer diagnosis and two small RNAs (EBER-1 and EBER-2) for Epstein-Barr virus diagnosis using multiple diagnostic platforms, including fluorescence and colorimetric-based lateral flow systems. We also show that CRISPR-Cas13a Gemini System can knockdown two foreign genes (EGFP and mCherry transcripts) in mammalian cells simultaneously. These findings suggest the potential of highly effective and simultaneous detection of multiple biomarkers and gene editing of multiple sites. CRISPR-Cas13a based methods currently use contiguous target RNA activation, which only enables single-target detection or editing. Here the authors propose a noncontiguous target RNA activation approach which can provide rapid, simultaneous and sensitive detection of two RNAs in a single readout, as well as parallel dual transgene knockdown. [ABSTRACT FROM AUTHOR]

Nearly one in five U.S. adults are impacted by long Covid. The health, social, and economic burdens of long Covid are complicated and trying. Although the causes of long Covid remain uncertain, emerging research suggests an infectious disease origin for at least some portion of cases. We draw on a grey and white literature, media reports, and postings on forums to examine the shared experiences of long Covid and the present argument for pathogen-pathogen interactions. Data suggest that long Covid disproportionately impacts communities that already experience disparities in health, specifically lower-educated, low-income, women of working age and minority ethnic groups as they have greater exposure to COVID-19 initially and experience the symptoms of long Covid more severely. Among these individuals, COVID-19 can play a role in reactivating viruses already present in the body (specifically herpesviruses) which accumulate over the course of a lifetime and generally persist in a dormant state. As such, long Covid may present as a syndemic in some communities – the clustering of synergistically interacting diseases, a consequence of deleterious social conditions. The syndemic nature of long Covid requires a syndemic response to address the intersecting social and biological drivers. At the population level, considerations of the social factors, disease co-morbidities including those dormant or yet to be diagnosed, need to be integrated into treatment protocols and public health responses. [ABSTRACT FROM AUTHOR]

The presence of oral microbes in extra-oral sites is linked to gastrointestinal cancers. However, their potential ectopically colonization in the nasopharynx and impact on local cancer development remains uncertain. Our study involving paired nasopharyngeal-oral microbial samples from nasopharyngeal carcinoma (NPC) patients and controls unveils an aberrant oral-to-nasopharyngeal microbial translocation associated with increased NPC risk (OR = 4.51, P = 0.012). Thirteen species are classified as oral-translocated and enriched in NPC patients. Among these, Fusobacterium nucleatum and Prevotella intermedia are validated through culturomics and clonal strain identification. Nasopharyngeal biopsy meta-transcriptomes confirm these microbes within tumors, influencing local microenvironment and cytokine response. These microbes correlate significantly with the Epstein-Barr virus (EBV) loads in the nasopharynx, exhibiting an increased dose-response relationship. Collectively, our study identifies oral microbes migrating to the nasopharynx, infiltrating tumors, impacting microenvironments and linking with EBV infection. These results enhance our understanding of abnormal microbial communication and their roles in carcinogenesis. Oral microbes in non-oral locations are noted across various cancers. This study highlights the abnormal translocation of oral microbes to the nasopharynx, raising the risk of nasopharyngeal cancer by remodeling the tumor microenvironment and potentially influencing EBV infection. [ABSTRACT FROM AUTHOR]

The presence of oral microbes in extra-oral sites is linked to gastrointestinal cancers. However, their potential ectopically colonization in the nasopharynx and impact on local cancer development remains uncertain. Our study involving paired nasopharyngeal-oral microbial samples from nasopharyngeal carcinoma (NPC) patients and controls unveils an aberrant oral-to-nasopharyngeal microbial translocation associated with increased NPC risk (OR = 4.51, P = 0.012). Thirteen species are classified as oral-translocated and enriched in NPC patients. Among these, Fusobacterium nucleatum and Prevotella intermedia are validated through culturomics and clonal strain identification. Nasopharyngeal biopsy meta-transcriptomes confirm these microbes within tumors, influencing local microenvironment and cytokine response. These microbes correlate significantly with the Epstein-Barr virus (EBV) loads in the nasopharynx, exhibiting an increased dose-response relationship. Collectively, our study identifies oral microbes migrating to the nasopharynx, infiltrating tumors, impacting microenvironments and linking with EBV infection. These results enhance our understanding of abnormal microbial communication and their roles in carcinogenesis. Oral microbes in non-oral locations are noted across various cancers. This study highlights the abnormal translocation of oral microbes to the nasopharynx, raising the risk of nasopharyngeal cancer by remodeling the tumor microenvironment and potentially influencing EBV infection. [ABSTRACT FROM AUTHOR]

The strategies adopted by viruses to reprogram the translation and protein quality control machinery and promote infection are poorly understood. Here, we report that the viral ubiquitin deconjugase (vDUB)—encoded in the large tegument protein of Epstein-Barr virus (EBV BPLF1)—regulates the ribosomal quality control (RQC) and integrated stress responses (ISR). The vDUB participates in protein complexes that include the RQC ubiquitin ligases ZNF598 and LTN1. Upon ribosomal stalling, the vDUB counteracts the ubiquitination of the 40 S particle and inhibits the degradation of translation-stalled polypeptides by the proteasome. Impairment of the RQC correlates with the readthrough of stall-inducing mRNAs and with activation of a GCN2-dependent ISR that redirects translation towards upstream open reading frames (uORFs)- and internal ribosome entry sites (IRES)-containing transcripts. Physiological levels of active BPLF1 promote the translation of the EBV Nuclear Antigen (EBNA)1 mRNA in productively infected cells and enhance the release of progeny virus, pointing to a pivotal role of the vDUB in the translation reprogramming that enables efficient virus production. Here, the authors show how the vDUB from the large tegument protein from the human herpes virus can reprogram translation in host cells by modulating the activity of the ribosome quality machinery and activating the integrated stress response. [ABSTRACT FROM AUTHOR]

Objectives: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening condition affecting young children. It is potentially triggered by Epstein-Barr virus (EBV). This study describes the neuroradiological features observed in 75 children with genetically confirmed primary HLH, comparing EBV-induced with non-EBV-induced HLH forms. Methods: Brain MRIs between 2007 and 2021 from 75 children with HLH according to the 2004 Histiocyte Society criteria and with a confirmed HLH-related mutation, were retrospectively reviewed by two pediatric neuroradiologists blinded to EBV status and to mutation status. At diagnosis, 17 children with EBV viremia above a threshold of 1000 copies/mL were included in the EBV-induced HLH group. The remaining 58 patients were included in the non-EBV-induced HLH group. Results: Of the 75 children initially included, 21 had abnormal MRI (21/75 (28%); 9/17 in the EBV-induced HLH group and 12/58 in the non-EBV-induced HLH group). All patients with abnormal MRI had neurological symptoms. Abnormal MRIs showed white matter lesions; the posterior fossa was affected in all but one case. There was no significant difference between groups regarding the localization or morphology of white matter lesions. The striatum was more frequently affected in the EBV-induced HLH group (8/9 (89%) versus 1/12 (8%), p = 0.00037). All lesions, whether in the white matter or in the basal ganglia, presented increased ADC values on diffusion weighted imaging (DWI). Conclusion: In this study of 75 children with genetically confirmed HLH, only children with neurological signs had abnormal brain MRI. Bilateral striatum involvement suggested an EBV-induced form of HLH. Key Points: • In children with genetically proven HLH, only those with neurological signs did have brain abnormalities at MRI. • All patients with abnormal brain MRI had multiple white matter lesions with increased ADC values, including in the posterior fossa in almost all cases. • Basal ganglia and in particular the striatum were bilaterally and symmetrically affected in almost all EBV-induced HLH patients, in contrast to the non-EBV-induced HLH patients. [ABSTRACT FROM AUTHOR]

Background: Stromal interaction molecule 1 (STIM1)-mediated Ca2+ signaling regulates tumor angiogenesis in nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-related human malignancy. However, the mechanism by which STIM1 modulates endothelial functional phenotypes contributing to tumor angiogenesis remains elusive. Methods: NPC cell-derived exosomes were isolated via differential centrifugation and observed using transmission electron microscopy. Exosome particle sizes were assessed by nanoparticle tracking analysis (NTA). Uptake of exosomes by recipient ECs was detected by fluorescent labeling of the exosomes with PKH26. Tumor angiogenesis-associated profiles were characterized by determining cell proliferation, migration, tubulogenesis and permeability in human umbilical vein endothelial cells (HUVECs). Activation of the Akt/ERK pathway was assessed by detecting the phosphorylation levels using Western blotting. A chick embryo chorioallantoic membrane (CAM) xenograft model was employed to study tumor-associated neovascularization in vivo. Results: We found that NPC cell-derived exosomes harboring EBV-encoded latent membrane protein 1 (LMP1) promoted proliferation, migration, tubulogenesis and permeability by activating the Akt/ERK pathway in ECs. STIM1 silencing reduced LMP1 enrichment in NPC cell-derived exosomes, thereby reversing its pro-oncogenic effects in an Akt/ERK pathway-dependent manner. Furthermore, STIM1 knockdown in NPC cells blunted tumor-induced vascular network formation and inhibited intra-tumor neovascularization in the chorioallantoic membrane (CAM) xenograft model. Conclusion: STIM1 regulates tumor angiogenesis by controlling exosomal EBV-LMP1 delivery to ECs in the NPC tumor microenvironment. Blocking exosome-mediated cell-to-cell horizontal transfer of EBV-associated oncogenic signaling molecules may be an effective therapeutic strategy for NPC. [ABSTRACT FROM AUTHOR]

The critical Epstein‒Barr virus (EBV)-encoded latent membrane protein 1 (LMP-1) and BamHI fragment H rightward open reading frame 1 (BHRF-1) genes affect EBV-mediated malignant transformation and virus replication during EBV infection. Therefore, these two genes are considered ideal targets for EBV vaccine development. However, gene mutations in LMP-1 and BHRF-1 in different cohorts may affect the biological functions of EBV, which would seriously hinder development of personalized vaccines for EBV. In the present study, by performing nested polymerase chain reaction (nested PCR) and DNA sequence techniques, we analyzed the nucleotide variability and phylogeny of LMP-1 containing a 30 bp deletion region (del-LMP-1) and BHRF-1 in EBV-infected patients (N = 382) and healthy persons receiving physical examination (N = 98; defined as the control group) in Yunnan Province, China. Three BHRF-1 subtypes were identified in this study: 79V88V, 79L88L, and 79V88L, with mutation frequencies of 58.59%, 24.24%, and 17.17%, respectively. Compared with the control group, the distribution of BHRF-1 subtypes of the three groups showed no significant difference, suggesting that BHRF-1 is highly conserved in EBV-related samples. In addition, a short fragment of del-LMP-1 was found in 133 cases, and the nucleotide variation rate was 87.50% (133/152). For del-LMP-1, a significant distribution in three groups was detected, as characterized by a high mutation rate. In conclusion, our study illustrates gene variability and mutations of EBV-encoded del-LMP-1 and BHRF-1 in clinical samples. Highly mutated LMP-1 might be associated with various types of EBV-related diseases, indicating that BHRF-1 combined with LMP-1 may be used as an ideal target for development of EBV personalized vaccines. [ABSTRACT FROM AUTHOR]

Purpose: Several outbreaks of acute hepatitis of unknown etiology (AHUE) in children were reported in 2022 in many countries, with adenovirus identified as the etiological agent in most of them. We aimed to evaluate the characteristics and outcomes of AHUE cases in Egypt. Methodology: Hospitalized patients with acute hepatitis were included in the study. Drug-induced, alcoholic hepatitis, autoimmune hepatitis, and Wilson's disease were identified either by medical history or by routine laboratory diagnosis. Molecular and serological approaches were used to investigate common viral causes of hepatitis, such as hepatitis A–E viruses, cytomegalovirus, Epstein–Barr virus, herpes simplex viruses (HSV1/2), adenovirus, parvovirus B19, and coxsackie virus. Results: A total of 42 patients were recruited and divided into two groups: 24 cases of unknown hepatitis after excluding the common causes and 18 cases of known hepatitis. About two-thirds of the patients were male (61.9%), and the mean age was 34.55 ± 16.27 years. Jaundice, dark urine, abdominal pain and diarrhea were recorded at a higher incidence in group 1, while jaundice and fever were frequent in group 2. Fulminant hepatitis occurred in 28.6% of the cases, but the two groups did not differ significantly in terms of patient outcome, duration of hospitalization, ascites, and development of fulminant hepatitis. Adenovirus was detected in five cases (20.8%) in group 1, and one case co-infecting with hepatitis E virus in group 2. Herpes simplex virus 1/2, coxsackie virus, and parvovirus B19 were not detected in any case, while etiologies of 75% of the cases were still not confirmed. One out of the six adenovirus-infected patients died. The outcome significantly correlated with the severity of the liver disease. Conclusion: This is the first report describing etiologies and characteristics of AHUE cases in Egypt, and interestingly, adenovirus was detected in adults. Further studies are required to determine the prevalence of this newly emerging viral hepatitis pathogens. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) is known to alter circulating effector memory or re-expressing CD45RA+ (TemRA) T-cell numbers, but whether Epstein–Barr virus (EBV) does the same or this is amplified during a CMV and EBV co-infection is unclear. Immune cell numbers in blood of children and young, middle-aged, and senior adults (n = 336) were determined with flow cytometry, and additional multivariate linear regression, intra-group correlation, and cluster analyses were performed. Compared to non-infected controls, CMV-seropositive individuals from all age groups had more immune cell variance, and CMV+ EBV− senior adults had more late-differentiated CD4+ and CD8+ TemRA and CD4+ effector memory T-cells. EBV-seropositive children and young adults had a more equal immune cell composition than non-infected controls, and CMV− EBV+ senior adults had more intermediate/late-differentiated CD4+ TemRA and effector memory T-cells than non-infected controls. CMV and EBV co-infected young and middle-aged adults with an elevated BMI and anti-CMV antibody levels had a similar immune cell composition as senior adults, and CMV+ EBV+ middle-aged adults had more late-differentiated CD8+ TemRA, effector memory, and HLA-DR+ CD38− T-cells than CMV+ EBV− controls. This study identified changes in T-cell numbers in CMV- or EBV-seropositive individuals and that some CMV and EBV co-infected young and middle-aged adults had an aging-related T-cell phenotype. [ABSTRACT FROM AUTHOR]

Lymphomatoid granulomatosis is a very rare B cell lymphoproliferative disease associated with Epstein–Barr virus infection. It is related to states of immunosuppression and affects the lung in more than 90% of cases, forcing the clinician to establish a differential diagnosis with other diseases such as infections, Wegener's granulomatosis, lymphoma, or lung metastases. There is no standard treatment for this disease. In this paper, we describe a rare case of a patient with grade 3 lymphomatoid granulomatosis with newly diagnosed HIV infection who started antiretroviral treatment with a gradual improvement of the lesions. [ABSTRACT FROM AUTHOR]

Introduction: Following hematopoietic stem cell transplantation or solid organ transplantation, patients are at risk of developing Epstein–Barr virus-positive post-transplant lymphoproliferative disease (EBV+ PTLD), which is an ultra-rare and potentially lethal hematologic malignancy. Common treatments for EBV+ PTLD include rituximab alone or combined with chemotherapy. Given specific considerations for this population, including severity of the underlying condition requiring transplant, the rigors of the transplant procedure, as well as risks to the transplanted organ, there is a group of patients with EBV+ PTLD for whom chemotherapy may be inappropriate; however, there is limited information characterizing these patients. This study aimed to reach expert consensus on the key characteristics of patients for whom chemotherapy may be inappropriate in a real-world setting. Methods: A two-round modified Delphi study was conducted to reach consensus among clinicians with expertise treating EBV+ PTLD. Articles identified in a targeted literature review guided the development of round 1 and 2 topics and related statements. The consensus threshold for round 1 statements was 75.0%. If consensus was achieved in round 1, the statement was not discussed further in round 2. The consensus thresholds for round 2 were moderate (62.5–75.0%), strong (87.5%), or complete (100.0%). Results: The panel was composed of a total of eight clinicians (seven hematologists/hemato-oncologists) from six European countries. The panel generated a final list of 43 consensus recommendations on the following topics: terminology used to describe patients for whom chemotherapy may be inappropriate; demographic characteristics; organ transplant characteristics; comorbidities that preclude the use of chemotherapy; EBV+ PTLD characteristics; and factors related to treatment-related mortality and morbidity. Conclusions: This modified Delphi panel successfully achieved consensus on key topics and statements that characterized patients with EBV+ PTLD for whom chemotherapy may be inappropriate. These recommendations will inform clinicians and aid in the treatment of EBV+ PTLD. [ABSTRACT FROM AUTHOR]

Background: Gianotti–Crosti syndrome is characterized by an acute onset of a papular or papulovesicular eruption with a symmetrical distribution. Data sources: A PubMed search was conducted using Clinical Queries with the key terms "Gianotti-Crosti syndrome" OR "papular acrodermatitis". The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews. This paper is based on, but not limited to, the search results. Results: The eruption of Gianotti–Crosti syndrome is found predominantly on the cheeks, extensor surfaces of the extremities, and buttocks. There is a sparing of antecubital and popliteal fossae as well as palms, soles, and mucosal surfaces. Although often asymptomatic, the lesions may be mildly to moderately pruritic. Gianotti–Crosti syndrome is most common in children between 1 and 6 years of age. The Epstein–Barr virus and the hepatitis B virus are the most common pathogens associated with Gianotti–Crosti syndrome. No treatment for Gianotti–Crosti syndrome is necessary because it is self-limited. In an era of vaccine hesitancy and refusal, Gianotti–Crosti syndrome may be important to mention to parents, because it can occur and trigger alarmism. Conclusions: Gianotti–Crosti syndrome is mainly a disease of early childhood, characterized by an acute onset of a papular or papulovesicular eruption with a symmetrical distribution. With the advent of more universal vaccination against hepatitis B virus, Epstein–Barr virus has become the most common etiologic agent of Gianotti–Crosti syndrome. Few cases of post-vaccination Gianotti–Crosti syndrome have been reported. Currently, the emphasis should be placed on its self-limiting attribution. [ABSTRACT FROM AUTHOR]

The detection of Epstein–Barr virus (EBV) in gastric cancer patients is crucial for clinical decision making, as it is related with specific treatment responses and prognoses. Despite its importance, the limited medical resources preclude universal EBV testing. Herein, we propose a deep learning-based EBV prediction method from H&E-stained whole-slide images (WSI). Our model was developed using 319 H&E stained WSI (26 EBV positive; TCGA dataset) from the Cancer Genome Atlas, and 108 WSI (8 EBV positive; ISH dataset) from an independent institution. Our deep learning model, EBVNet consists of two sequential components: a tumor classifier and an EBV classifier. We visualized the learned representation by the classifiers using UMAP. We externally validated the model using 60 additional WSI (7 being EBV positive; HGH dataset). We compared the model's performance with those of four pathologists. EBVNet achieved an AUPRC of 0.65, whereas the four pathologists yielded a mean AUPRC of 0.41. Moreover, EBVNet achieved an negative predictive value, sensitivity, specificity, precision, and F1-score of 0.98, 0.86, 0.92, 0.60, and 0.71, respectively. Our proposed model is expected to contribute to prescreen patients for confirmatory testing, potentially to save test-related cost and labor. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is reportedly the first identified human tumor virus, and is closely related to the occurrence and development of nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), and several lymphomas. PD-L1 expression is elevated in EBV-positive NPC and GC tissues; however, the specific mechanisms underlying the EBV-dependent promotion of PD-L1 expression to induce immune escape warrant clarification. EBV encodes 44 mature miRNAs. In this study, we find that EBV-miR-BART11 and EBV-miR-BART17-3p upregulate the expression of PD-L1 in EBV-associated NPC and GC. Furthermore, EBV-miR-BART11 targets FOXP1, EBV-miR-BART17-3p targets PBRM1, and FOXP1 and PBRM1 bind to the enhancer region of PD-L1 to inhibit its expression. Therefore, EBV-miR-BART11 and EBV-miR-BART17-3p inhibit FOXP1 and PBRM1, respectively, and enhance the transcription of PD-L1 (CD274, http://www.ncbi.nlm.nih.gov/gene/29126), resulting in the promotion of tumor immune escape, which provides insights into potential targets for EBV-related tumor immunotherapy. Epstein-Barr virus (EBV)-encoded latent genes are reported to regulate PD-L1 expression to promote immune escape. Here, the authors show that EBV-encoded miRNAs EBV-miR-BART11 and EBV-miR-BART17-3p upregulate PD-L1 expression in nasopharyngeal carcinoma and gastric cancer by targeting FOXP1 and PBRM1. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) persists in human B-cells by maintaining its chromatinized episomes within the nucleus. We have previously shown that cellular factor Poly [ADP-ribose] polymerase 1 (PARP1) binds the EBV genome, stabilizes CTCF binding at specific loci, and that PARP1 enzymatic activity correlates with maintaining a transcriptionally active latency program. To better understand PARP1's role in regulating EBV latency, here we functionally characterize the effect of PARP enzymatic inhibition on episomal structure through in situ HiC mapping, generating a complete 3D structure of the EBV genome. We also map intragenomic contact changes after PARP inhibition to global binding of chromatin looping factors CTCF and cohesin across the EBV genome. We find that PARP inhibition leads to fewer total unique intragenomic interactions within the EBV episome, yet new chromatin loops distinct from the untreated episome are also formed. This study also illustrates that PARP inhibition alters gene expression at the regions where chromatin looping is most effected. We observe that PARP1 inhibition does not alter cohesin binding sites but does increase its frequency of binding at those sites. Taken together, these findings demonstrate that PARP has an essential role in regulating global EBV chromatin structure and latent gene expression. Genome folding in the nucleus plays an important role in regulating gene expression. Here the authors show that 3D genome architecture also plays an important role for gene expression adaptability for the Epstein-Barr Virus (EBV), a virus that is associated with cancer. They also observe major changes in the fold of the EBV chromosome between silent and transcriptional active viral genomes. [ABSTRACT FROM AUTHOR]

The final paper discussed this month reports that an EBV transcription factor occupies a large number of the MS genetic risk variants and this may at least partly explain how EBV infection and genetic risk intersect to cause MS. To assess whether a confounder could independently lead to EBV infection and MS, seropositivity to CMV was tested, because CMV infection displays very similar epidemiology to EBV infection. The association between Epstein-Barr virus (EBV) and multiple sclerosis (MS) has been known for many years. [Extracted from the article]

Clinicopathological risk factors for a poor prognosis were investigated in elderly patients with malignant lymphoma of the central nervous system. A total of 82 pathologically confirmed, CD20-positive, diffuse large B-cell lymphoma patients aged 71 years or older who underwent therapeutic intervention in the Tohoku and Niigata area in Japan were retrospectively reviewed. A univariate analysis was performed by the log-rank test using the Kaplan–Meier method. A Cox proportional hazards model was used for multivariate analysis of risk factors. Of the 82 patients, 39 were male and 43 were female, and their median age at onset was 75 years. At the end of the study, there were 34 relapse-free patients (41.5%), 48 relapse cases (58.5%), median progression-free survival was 18 months, and median overall survival (OS) was 26 months; there were 41 deaths and 41 survivors. Multivariate analysis of median OS showed that Karnofsky Performance Status less than 60% 3 months after treatment (p = 0.022, hazard ratio (HR) = 2.591) was the clinical risk factor, and double expressor lymphoma (p = 0.004, HR = 3.163), expression of programmed death-ligand 1 in tumor infiltrating lymphocytes or tumor-associated macrophages (p < 0.001, HR = 5.455), and Epstein–Barr virus infection (p = 0.031, HR = 5.304) were the pathological risk factors. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus-associated gastric cancer (EBVaGC) shows a robust response to immune checkpoint inhibitors. Therefore, a cost-efficient and accessible tool is needed for discriminating EBV status in patients with gastric cancer. Here we introduce a deep convolutional neural network called EBVNet and its fusion with pathologists for predicting EBVaGC from histopathology. The EBVNet yields an averaged area under the receiver operating curve (AUROC) of 0.969 from the internal cross validation, an AUROC of 0.941 on an external dataset from multiple institutes and an AUROC of 0.895 on The Cancer Genome Atlas dataset. The human-machine fusion significantly improves the diagnostic performance of both the EBVNet and the pathologist. This finding suggests that our EBVNet could provide an innovative approach for the identification of EBVaGC and may help effectively select patients with gastric cancer for immunotherapy. Epstein–Barr virus-associated gastric cancer shows a robust response to immune checkpoint inhibitors. Here the authors introduce a deep convolutional neural network and its fusion with pathologists for predicting it from histopathology. [ABSTRACT FROM AUTHOR]

Although recent work has described the microbiome in solid tumors, microbial content in hematological malignancies is not well-characterized. Here we analyze existing deep DNA sequence data from the blood and bone marrow of 1870 patients with myeloid malignancies, along with healthy controls, for bacterial, fungal, and viral content. After strict quality filtering, we find evidence for dysbiosis in disease cases, and distinct microbial signatures among disease subtypes. We also find that microbial content is associated with host gene mutations and with myeloblast cell percentages. In patients with low-risk myelodysplastic syndrome, we provide evidence that Epstein-Barr virus status refines risk stratification into more precise categories than the current standard. Motivated by these observations, we construct machine-learning classifiers that can discriminate among disease subtypes based solely on bacterial content. Our study highlights the association between the circulating microbiome and patient outcome, and its relationship with disease subtype. Circulating microbiome has been very little studied for blood malignancies. Here, the authors show specific microbiome signatures in the blood are associated with different types of myeloid malignancies and specific genetic mutations. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is reportedly the first identified human tumor virus, and is closely related to the occurrence and development of nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), and several lymphomas. PD-L1 expression is elevated in EBV-positive NPC and GC tissues; however, the specific mechanisms underlying the EBV-dependent promotion of PD-L1 expression to induce immune escape warrant clarification. EBV encodes 44 mature miRNAs. In this study, we find that EBV-miR-BART11 and EBV-miR-BART17-3p upregulate the expression of PD-L1 in EBV-associated NPC and GC. Furthermore, EBV-miR-BART11 targets FOXP1, EBV-miR-BART17-3p targets PBRM1, and FOXP1 and PBRM1 bind to the enhancer region of PD-L1 to inhibit its expression. Therefore, EBV-miR-BART11 and EBV-miR-BART17-3p inhibit FOXP1 and PBRM1, respectively, and enhance the transcription of PD-L1 (CD274, http://www.ncbi.nlm.nih.gov/gene/29126), resulting in the promotion of tumor immune escape, which provides insights into potential targets for EBV-related tumor immunotherapy. Epstein-Barr virus (EBV)-encoded latent genes are reported to regulate PD-L1 expression to promote immune escape. Here, the authors show that EBV-encoded miRNAs EBV-miR-BART11 and EBV-miR-BART17-3p upregulate PD-L1 expression in nasopharyngeal carcinoma and gastric cancer by targeting FOXP1 and PBRM1. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) persists in human B-cells by maintaining its chromatinized episomes within the nucleus. We have previously shown that cellular factor Poly [ADP-ribose] polymerase 1 (PARP1) binds the EBV genome, stabilizes CTCF binding at specific loci, and that PARP1 enzymatic activity correlates with maintaining a transcriptionally active latency program. To better understand PARP1's role in regulating EBV latency, here we functionally characterize the effect of PARP enzymatic inhibition on episomal structure through in situ HiC mapping, generating a complete 3D structure of the EBV genome. We also map intragenomic contact changes after PARP inhibition to global binding of chromatin looping factors CTCF and cohesin across the EBV genome. We find that PARP inhibition leads to fewer total unique intragenomic interactions within the EBV episome, yet new chromatin loops distinct from the untreated episome are also formed. This study also illustrates that PARP inhibition alters gene expression at the regions where chromatin looping is most effected. We observe that PARP1 inhibition does not alter cohesin binding sites but does increase its frequency of binding at those sites. Taken together, these findings demonstrate that PARP has an essential role in regulating global EBV chromatin structure and latent gene expression. Genome folding in the nucleus plays an important role in regulating gene expression. Here the authors show that 3D genome architecture also plays an important role for gene expression adaptability for the Epstein-Barr Virus (EBV), a virus that is associated with cancer. They also observe major changes in the fold of the EBV chromosome between silent and transcriptional active viral genomes. [ABSTRACT FROM AUTHOR]

At present, studies have found that latent Epstein-Barr virus (EBV) infection is associated with a variety of human tumours, and a vaccine is not available in this field. In this research, RT–PCR was used to obtain BZLF1 (immediately expressed early antigen Z) and LMP2 (latent membrane protein 2) cDNA from EBV. A ZLP2 fusion gene containing a linker sequence that encoded the polypeptide (Gly4Ser)3 was obtained using the sequence splicing overlap extension method. Then, ZLP2 was inserted into pMV261 cells, and the recombinant plasmid pMV-ZLP2 was transformed into BCG competent cells. After EB virus-positive tumour cell (NPRC18) cancer models were established with C57BL/6 J mice, tumour weight, tumour formation time and mouse survival conditions were analyzed, and flow cytometry was used to analyze the quantities of CD8 + and CD4 + T cells. HE staining was used to detect and analyze lymphocyte infiltration, and statistical analysis was used to analyze the immunological effect of recombinant BCG (rBCG). Compared with the control group, rBCG could significantly prolong the survival time of mice, slow tumour growth and delay tumour formation time. Recombinant BCG exhibits an obvious immune effect in mice and an inhibitory effect on EBV-positive cancer. Key points • AZLP2 fusion gene with BZLF1 and LMP2 of EB virus was constructed. • ZLP2 fusion gene was expressed with rBCG. • rBCG with ZLP2 has an obvious effect on EBV-positive cancer. [ABSTRACT FROM AUTHOR]

T cell responses to Kaposi's sarcoma-associated herpesvirus (KSHV) are likely essential in the control of KSHV infection and protection from associated disease, but remain poorly characterised. KSHV prevalence in rural Uganda is high at >90%. Here we investigate IFN- γ T cell responses to the KSHV proteome in HIV-negative individuals from a rural Ugandan population. We use an ex-vivo IFN- γ ELISpot assay with overlapping peptide pools spanning 83 KSHV open reading frames (ORF) on peripheral blood mononuclear cells (PBMC) from 116 individuals. KSHV-specific T cell IFN- γ responses are of low intensity and heterogeneous, with no evidence of immune dominance; by contrast, IFN- γ responses to Epstein–Barr virus, Cytomegalovirus and influenza peptides are frequent and intense. Individuals with KSHV DNA in PBMC have higher IFN- γ responses to ORF73 (p = 0.02) and lower responses to K8.1 (p = 0.004) when compared with those without KSHV DNA. In summary, we demonstrate low intensity, heterogeneous T cell responses to KSHV in immune-competent individuals. The T cell response to Kaposi sarcoma-associated herpesvirus is critical to controlling infection and immunopathology but has been poorly explored in immunocompetent patients. Here the authors characterise the T cell response to the Kaposi sarcoma-associated herpesvirus proteome in immunocompetent patients from rural Uganda. [ABSTRACT FROM AUTHOR]

Primary intracranial smooth muscle tumors are rare. Most cases are related to Epstein-Barr virus proliferation in immunocompromised patients such as organ solid recipients. Only a few cases have been reported in pediatric patients. The clinical features are very variable depending mainly on the location and size of the smooth muscle tumor (SMT) and the pathogenesis is poorly understood. We describe two cases of intracranial SMT localized in the temporal lobe and associated with EBV in immunosuppressed children. A review of the literature associated with intracranial leiomyomas was also done. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is an oncogenic herpesvirus implicated in the pathogenesis of several malignant and non-malignant conditions. However, a number of fundamental aspects about the biology of EBV and the mechanism(s) by which this virus induces pathology remain unknown. One major obstacle has been the lack of a suitable animal model for EBV infection. In this study, using our recently established rabbit model of EBV infection, we examined the early events following primary EBV infection. We show that, both immunocompetent and immunosuppressed animals were readily susceptible to EBV infection. However, immunosuppressed animals showed marked splenomegaly and widespread infection. Following EBV infection, the virus primarily targeted naïve IgM+, CD20+, CD21+ and CD79a+ B cells. Infected cells expressed varying sets of viral latent/lytic gene products. Notably, co-expression of latent and lytic proteins in the same cell was not observed. Infected cells in type 0/1 latency (EBERs+), were small and proliferating (Ki67+). By contrast, cells in type 2/3 latency (LMP1+), were large, non-proliferating (Ki-67−) and p53+. Although infected B-cells were widely present in splenic follicles, they did not express germinal center marker, BCL-6. Taken together, this study shows for the first time, some of the early events following primary EBV infection. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to assess the presence of herpesviruses and periodontopathic bacteria and to establish their potential association with pericoronitis. Materials and methods: Fifty samples obtained with paper points (30 from pericoronitis and 20 controls) were subjected to polymerase chain reaction (PCR) analysis. A single-stage and nested PCR assays were used to detect herpesviruses: human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) and six periodontopathic anaerobic bacteria: Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Parvimonas micra, Treponema denticola, and Tannarella forsythia. Results: Pericoronitis samples harbored HCMV and EBV at significantly higher rates than the control group (70 vs. 40 % and 46.7 vs. 15 %, P = 0.035, P = 0.021, respectively). P. micra and T. forsythia (66.7 vs. 0 %, and 40 vs. 10 %, P = 0.001, P = 0.021, respectively) were significantly more common in pericoronitis compared to the control group. Multivariate logistic regression analysis showed that the presence of T. forsythia was associated with pericoronitis development (OR 7.3, 95 % CI, 1.2-43.2, P = 0.028). Conclusion: The occurrence of HCVM and EBV extends our previous knowledge on microbiota in pericoronitis. These PCR-based findings demonstrated that bacterial and viral DNA occurred concomitantly in pericoronitis samples. T. forsythia appeared to be significantly associated with pericoronitis development in the examined sample. Clinical relevance: Herpesviral-bacterial co-infections might exacerbate the progression of pericoronitis. [ABSTRACT FROM AUTHOR]

Background and aims: Epstein–Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is the most common EBV-associated cancer and accounts for ~ 10% of all gastric cancers (GC). Epstein–Barr virus nuclear antigen 1 (EBNA1), which is critical for the replication and maintenance of the EBV latent genome, is consistently expressed in all EBVaGC tumors. We previously developed small molecule inhibitors of EBNA1. In this study, we investigated the efficacy and selectivity of an EBNA1 inhibitor in cell-based and animal xenograft models of EBV-positive and EBV-negative gastric carcinoma. Methods: We tested the potency of an EBNA1 inhibitor, VK-1727, in vitro and in xenograft studies, using EBV-positive (SNU719 and YCCEL1) and EBV-negative (AGS and MKN74) GC cell lines. After treatment, we analyzed cell viability, proliferation, and RNA expression of EBV genes by RT-qPCR. Results: Treatment with VK-1727 selectively inhibits cell cycle progression and proliferation in vitro. In animal studies, treatment with an EBNA1 inhibitor resulted in a significant dose-dependent decrease in tumor growth in EBVaGC xenograft models, but not in EBV-negative GC xenograft studies. Gene expression analysis revealed that short term treatment in cell culture tended towards viral gene activation, while long-term treatment in animal xenografts showed a significant decrease in viral gene expression. Conclusions: EBNA1 inhibitors are potent and selective inhibitors of cell growth in tissue culture and animal models of EBV-positive GC. Long-term treatment with EBNA1 inhibitors may lead to loss of EBV in mouse xenografts. These results suggest that pharmacological targeting of EBNA1 may be an effective strategy to treat patients with EBVaGC. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to evaluate the utility of metagenomic next-generation sequencing (mNGS) for the diagnosis of Pneumocystis jirovecii pneumonia (PJP) in non-human immunodeficiency virus-infected patients. Methods: We conducted a retrospective study. A total of 60 non-human immunodeficiency virus-infected PJP patients and 134 patients diagnosed with non-PJP pneumonia were included. P. jirovecii and other co-pathogens identified by mNGS in bronchoalveolar lavage fluid and/or blood samples were analyzed. Using clinical composite diagnosis as the reference standard, we compared the diagnostic performance of mNGS in PJP with conventional methods, including Gomori methenamine silver staining and serum (1,3)-β-d-glucan. Modifications of antimicrobial treatment for PJP patients after the report of mNGS results were also reviewed. Results: mNGS reached a sensitivity of 100% in diagnosing PJP, which was remarkably higher than Gomori methenamine silver staining (25.0%) and serum (1,3)-β-d-glucan (67.4%). The specificity of mNGS (96.3%) significantly surpassed serum (1,3)-β-d-glucan (81.4%). Simultaneous mNGS of bronchoalveolar lavage fluid and blood samples was performed in 21 out of 60 PJP patients, and it showed a concordance rate of 100% in detecting P. jirovecii. Besides, mNGS showed good performance in identifying co-pathogens of PJP patients, among which cytomegalovirus and Epstein-Barr virus were most commonly seen. Initial antimicrobial treatment was modified in 71.7% of PJP patients after the report of mNGS results. Conclusion: mNGS is a useful diagnostic tool with good performance for the diagnosis of PJP and the detection of co-pathogens. mNGS of bronchoalveolar lavage fluid and/or blood samples is suggested in patients with presumptive diagnosis of PJP. Blood samples may be a good alternative to bronchoalveolar lavage fluid for mNGS when bronchoscopic examination is not feasible. [ABSTRACT FROM AUTHOR]

Using Epstein-Barr virus (EBV)-based markers to screen populations at high risk for nasopharyngeal carcinoma (NPC) is an attractive preventive approach. Here, we develop a comprehensive risk score (CRS) that combines risk effects of EBV and human genetics for NPC risk stratification and validate this CRS within an independent, population-based dataset. Comparing the top decile with the bottom quintile of CRSs, the odds ratio of developing NPC is 21 (95% confidence interval: 12–37) in the validation dataset. When combining the top quintile of CRS with EBV serology tests currently used for NPC screening in southern China, the positive prediction value of screening increases from 4.70% (serology test alone) to 43.24% (CRS plus serology test). By identifying individuals at a monogenic level of NPC risk, this CRS approach provides opportunities for personalized risk prediction and population screening in endemic areas for the early diagnosis and secondary prevention of NPC. Epstein-Barr virus (EBV) is associated with high risk for nasopharyngeal carcinoma (NPC). Here, the authors develop a comprehensive risk score that combines risk effects of EBV and human genetics for NPC risk stratification. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus nuclear antigen 2 (EBNA2) is a transactivator of viral and cellular gene expression, which plays a critical role in the Epstein-Barr virus-associated diseases. It was reported that EBNA2 regulates gene expression by reorganizing chromatin and manipulating epigenetics. Recent studies showed that liquid-liquid phase separation plays an essential role in epigenetic and transcriptional regulation. Here we show that EBNA2 reorganized chromatin topology to form accessible chromatin domains (ACDs) of the host genome by phase separation. The N-terminal region of EBNA2, which is necessary for phase separation, is sufficient to induce ACDs. The C-terminal domain of EBNA2 promotes the acetylation of accessible chromatin regions by recruiting histone acetylase p300 to ACDs. According to these observations, we proposed a model of EBNA2 reorganizing chromatin topology for its acetylation through phase separation to explain the mechanism of EBNA2 hijacking the host genome by controlling its epigenetics. Yang et al find that phase separation of the Epstein-Barr virus nuclear antigen 2 (EBNA2) is involved in the formation of accessible chromatin domains of the host genome. They also find that EBNA2 recruits histone acetyltransferase to promote histone acetylation on accessible chromatin regions and regulate gene expression and that these two functions are performed by the N- and Cterminus respectively. [ABSTRACT FROM AUTHOR]

Human Cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) are endowed with the ability of establishing lifelong latency in human hosts and reactivating in immunocompromised subjects, including patients suffering from ulcerative colitis (UC). We, therefore, aimed to investigate virus-specific immunity in UC patients. A cohort of 24 UC patients (14 responders and 10 refractory to therapy) and 26 control subjects was prospectively enrolled to undergo virus-specific serology (by ELISA assay) and assessment of both CD4+ and CD8+ virus-specific T-cell response (by interferon-γ enzyme-linked immunospotanalysis). In parallel, mucosal viral load was determined by quantitative real-time PCR and the values were correlated with both clinical and endoscopic indexes of activity. For statistics, the t-test, Mann–Withney test, Fisher's exact test and Spearman rank correlation test were applied; p < 0.05 was considered significant. EBV-specific CD4+ and CD8+ T-cell responses were significantly lower in UC patients compared to controls (p < 0.0001 and p = 0.0006, respectively), whereas no difference was found for HCMV-specific T-cell response. When dividing the UC group according to response to therapy, both responders and refractory UC patients showed a deficient EBV-specific CD4+ T-cell response with respect to controls (p < 0.04 and p = 0.0003, respectively). Moreover, both EBV and HCMV mucosal loads were significantly higher in refractory UC than in responders and controls (p = 0.007 and 0.003; and p = 0.02 and 0.001, respectively), and correlated with activity indexes. Steroid therapy seemed the main risk factor for triggering EBV colitis. Finally, no cases of IgM positivity were found in the study population. An impaired EBV-specific immunity was clearly evident in UC patients, mostly in those refractory to therapy. The ELISPOT assay may serve as new tool for quantifying and monitoring virus-specific T-cell immunity in UC. [ABSTRACT FROM AUTHOR]

The objective of this study was to detect the Epstein–Barr virus (EBV) coinfection in coronavirus disease 2019 (COVID-19). In this retrospective single-center study, we included 67 COVID-19 patients with onset time within 2 weeks in Renmin Hospital of Wuhan University from January 9 to February 29, 2020. Patients were divided into EBV/SARS-CoV-2 coinfection group and SARS-CoV-2 infection alone group according to the serological results of EBV, and the characteristics differences between the two groups were compared. The median age was 37 years, with 35 (52.2%) females. Among these COVID-19 patients, thirty-seven (55.2%) patients were seropositive for EBV viral capsid antigen (VCA) IgM antibody. EBV/SARS-CoV-2 coinfection patients had a 3.09-fold risk of having a fever symptom than SARS-CoV-2 infection alone patients (95% CI 1.11–8.56; P = 0.03). C-reactive protein (CRP) (P = 0.02) and the aspartate aminotransferase (AST) (P = 0.04) in EBV/SARS-CoV-2 coinfection patients were higher than that in SARS-CoV-2 infection alone patients. EBV/SARS-CoV-2 coinfection patients had a higher portion of corticosteroid use than the SARS-CoV-2 infection alone patients (P = 0.03). We find a high incidence of EBV coinfection in COVID-19 patients. EBV/SARS-CoV-2 coinfection was associated with fever and increased inflammation. EBV reactivation may associated with the severity of COVID-19. [ABSTRACT FROM AUTHOR]

Plasma cell differentiation (PCD) is frequently observed in some entities of non-Hodgkin B cell lymphoma, including both low-grade and high-grade lymphomas. However, except for plasmablastic lymphoma and primary effusion lymphoma, EBV+ B cell lymphoproliferative disorder (LPD) with PCD has not been well addressed due to its rarity. We clinicopathologically examined five cases of nodal EBV+ polymorphic B cell LPD with PCD (PBLPD-PCD) initially diagnosed as polymorphic EBV+ diffuse large B cell lymphoma, not otherwise specified (DLBCL-NOS) with PCD (n = 3) and methotrexate-associated B cell LPD (MTX-associated B-LPD) (n = 2). One case had a concomitant brain lesion which was clinically diagnosed as EBV-related encephalitis. This patient received therapy with vidarabine, and both the brain lesion and the nodal EBV+ PBLPD-PCD lesions disappeared. Another case was characterized by Mott cell differentiation. This case was the first reported case of EBV+ B cell lymphoma or LPD with Mott cell differentiation. The two cases of MTX-associated B cell LPD which arose in patients with rheumatoid arthritis spontaneously regressed after MTX cessation. TCRγ and IGH PCR analysis was performed in four cases. Two cases had TCRγ rearrangements, but no IGH rearrangements. The other two cases had no rearrangements in these genes. We concluded that nodal EBV+ PBLPD-PCD is rare, with heterogeneous characteristics. PCR analysis revealed that nodal EBV+ PBLPD-PCD may have only TCR clonality and no IGH clonality. Considering the partial or complete loss of CD20 expression on the tumor cells, this result may be confusing for accurate diagnosis of EBV+ PBLPD-PCD, and pathologists need to be aware of this phenomenon to avoid misdiagnosis. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV), human herpesvirus 6A/B (HHV-6A/B) and multiple sclerosis (MS)-associated retrovirus (MSRV) have been described as possible MS triggers. We analysed antibody titres against EBV and HHV-6, and MSRV envelope (env) mRNA expression, in the serum of pregnant multiple sclerosis patients (P-MS) to study their possible link to the clinical activity of MS during pregnancy and postpartum and their possible role as relapse predictors. For that purpose, serum samples were collected from 71 pregnant women (50 pregnant MS and 21 pregnant healthy controls—P-HC) during pregnancy and postpartum. Relating to antibody titres, IgM antibody titres against HHV-6A/B were significantly higher in P-MS than in P-HC both in each pregnancy trimester and in the postpartum period. Moreover, IgM antibody titres against HHV-6A/B were higher in P-MS who suffered a relapse during the postpartum. Regarding MSRV env mRNA expression, the prevalence in the first trimester of pregnancy was significantly higher in P-MS who suffered relapses during pregnancy. Summing it up, high IgM antibody titres against HHV-6A/B and MSRV env mRNA expression during the first trimester of pregnancy could act as relapse predictors for the gestation/postpartum periods. [ABSTRACT FROM AUTHOR]

Background: The underlying etiology of juvenile dermatomyositis (JDM) is unknown. T cell deficiency as well as Epstein–Barr virus (EBV) infection had been suspected to be involved in the pathogenesis, but it has been poorly evaluated in JDM patients. Methods: This study described the traits of T and B lymphocyte subsets in newly onset JDM patients and the incidence of EBV infection in JDM patients compared with match controls. Newly developed JDM patients from 2014 to 2018 were included in the study. Lymphocytes with different markers (CD3+, CD3+CD4+, CD3+CD8+, CD3−CD19+ and CD3−CD16+CD56+) were tested with flow cytometry in the first admission or after 6 months of treatment. Statistical analysis was conducted to compare the EBV infection in the group of JDM patients and controls. Results: We observed that JDM patients had higher positive rate of Epstein–Barr nuclear antigen-immunoglobulin G (IgG) (P < 0.0001) as well as EBV capsid antigen-IgG (P < 0.05) than normal controls. CD3−CD16+CD56+ lymphocyte was found to be extremely low in early stage of JDM patients, but increased after 6 months of treatment (P = 0.0091). Conclusions: The level of CD3−CD16+CD56+ cells may associate with the clinical course of JDM. EBV may act as an environmental factor predisposing patients to the development of JDM. [ABSTRACT FROM AUTHOR]

A 78-year-old man with a subepithelial lesion (SEL) in the gastric body and two carcinomas in the gastric antrum was referred to our hospital. Following a diagnosis of SEL, the patient was followed-up by esophagogastroduodenoscopy annually for 4 years. Although the SEL had increased in size over the years, histological evaluation of the forceps biopsies did not reveal any significant findings. We detected a hypoechoic mass in the submucosa by endoscopic ultrasonography, and suspected the lesion to be an aberrant pancreas or mesenchymal tumor. The patient first underwent endoscopic submucosal dissection for the 2 gastric cancers. Histological examination of the resected specimens revealed intramucosal well-differentiated tubular adenocarcinomas. Next, endoscopic ultrasound–guided fine-needle aspiration (EUS-FNA) was performed for the gastric SEL. Aspirated specimens revealed an adenocarcinoma with lymphocyte infiltration. The lesion was diagnosed as a gastric carcinoma with lymphoid stroma (GCLS). Subsequently, he underwent distal gastrectomy, and the surgical specimen was confirmed as GCLS corresponding to preoperative diagnosis. In addition, the adenocarcinoma cells were positive for Epstein–Barr (EB) virus-encoded small RNA-1 by in situ hybridization. Finally, the lesion was diagnosed as GCLS associated with EB virus. Thus, EUS-FNA is advantageous for diagnosing GCLS associated with EB virus. [ABSTRACT FROM AUTHOR]

Epstein–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. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus-positive gastric cancer [EBV (+) GC] is a distinct GC subtype with unique genetic and epigenetic aberrations. Here, we examined resected GC samples and publicly available microarray data and The Cancer Genome Atlas (TCGA) database to identify the mechanism underlying overexpression of PD-L1 in EBV (+) GC. We found that high levels of PD-L1 overexpression in EBV (+) GC were caused by focal amplification of CD274. By contrast, relatively high expression of PD-L1 in tumor tissue and infiltrating immune cells correlated with CD8 lymphocyte infiltration and IFN-γ expression via IRF3 activation. Since we reported previously that PD-L1 expression is associated both with the presence of CD8 T cells in the tumor microenvironment and with IFN-γ expression in GC, we examined a database to see whether IFN-γ-associated overexpression of PD-L1 plays a significant role in EBV (+) GC. Immunohistochemical staining showed that expression of the IRF3 signature in clinical GC samples was higher in EBV (+) than in EBV (−) cases. The data presented herein reveal a unique dual mechanism underlying PD-L1 overexpression in EBV (+) GC: high focal amplification of CD274 or IFN-γ-mediated signaling via activation of IRF3. [ABSTRACT FROM AUTHOR]

Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies. Even in high-income countries the 5-year survival rate for stage IV NPC is less than 40%. Here we report high somatostatin receptor 2 (SSTR2) expression in multiple clinical cohorts comprising 402 primary, locally recurrent and metastatic NPCs. We show that SSTR2 expression is induced by the Epstein–Barr virus (EBV) latent membrane protein 1 (LMP1) via the NF-κB pathway. Using cell-based and preclinical rodent models, we demonstrate the therapeutic potential of SSTR2 targeting using a cytotoxic drug conjugate, PEN-221, which is found to be superior to FDA-approved SSTR2-binding cytostatic agents. Furthermore, we reveal significant correlation of SSTR expression with increased rates of survival and report in vivo uptake of the SSTR2-binding 68Ga-DOTA-peptide radioconjugate in PET-CT scanning in a clinical trial of NPC patients (NCT03670342). These findings reveal a key role in EBV-associated NPC for SSTR2 in infection, imaging, targeted therapy and survival. Nasopharyngeal carcinoma (NPC) lacks effective diagnostic and therapeutic strategies, in particular at advanced stages. Here, the authors show that expression of the somatostatin receptor 2 is induced by Epstein-Barr virus in NPC and has a key role in the diagnosis, imaging, targeted therapies and prognosis of NPC. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the association of Epstein-Barr virus (EBV) with peripheral blood immune cell counts and clinical outcomes in advanced nasopharyngeal carcinoma (NPC) patients. In a retrospective design, 146 patients with NPC at stage IV were enrolled in this study. The association of EBV status with peripheral blood immune cell counts, distant metastases, and long-term survival in patients with advanced NPC were determined. Eighty-seven (59.6%) of all patients were positive for EBV. Compared with patients with normal NK cell count, patients with lower NK cell count showed a significantly lower EBV viral load (median: 614.0 vs. 2190.0 copies/mL, P = 0.024). EBV-positive patients showed a significantly higher incidence of liver metastasis than EBV-negative patients (32.6% vs. 23.7%, P = 0.021). Multi-variant regression analysis showed that EBV infection was independently associated with liver metastasis (OR: 2.33, P = 0.043). EBV positive patients showed a significantly worse PFS (P = 0.001) and OS (P = 0.001) than EBV negative patients. Multivariate Cox regression analysis revealed that EBV infection was independently associated with a worse PFS (HR: 1.94, P = 0.003), and OS (HR: 2.12, P = 0.014) in advanced NPC. In conclusion, EBV infection is associated with a high risk of liver metastasis and is also an independent negative predictor for PFS and OS in patients with advanced NPC. EBV infection is associated with lower CD8% and higher NK%, while lower NK cell count is associated with lower EBV viral load. [ABSTRACT FROM AUTHOR]

The rise in business and electronic transactions using the web as a medium has driven the widespread use of recommendation systems across all domains. Recommendation systems generate suggestions for the travel and tourism industry, particularly hotels or services, centered on user interests and preferences. Relevant information collection, organization, processing vast quantities of string data, efficient data retrieval, and computational complexity in handling information overload are key issues to be addressed in a recommendation system. This work proposes a novel approach, using encoded bit vectors, to process information on hotel amenities and features extracted from Tripadvisor. Hotel amenities at different locations are organized and stored, based on the priority of the location, using the most significant bit and least significant bit. The amenities are prioritized dynamically thereafter, based on the location, and unique amenities accorded greater preference than the ones routinely offered at most hotels. Encoded bit vectors are utilized for information retrieval and precise hotel recommendations made, based on user interest rather than the string processing method that is ineffective where scalable data are concerned. Finally, the recommended hotels are ranked with user-centric personalized recommendations. These high-speed, efficient, and scalable algorithms are ideal for incrementally updating data. They also facilitate fast, flawless IR and query processing, along with appropriate hotel recommendations. The theoretical evaluation shows that the proposed method aids quick query processing and retrieval. The experimental assessment shows that hotels recommended by the proposed bit vector recommendation system have a higher accuracy on par with user and expert recommendations. [ABSTRACT FROM AUTHOR]

Purpose: Anatomical imaging criteria for the diagnosis of malignant head and neck nodes may not always be reliable. This study aimed to evaluate the diagnostic value of conventional diffusion-weighted imaging (DWI) and intravoxel incoherent motion (IVIM) DWI in discriminating benign and malignant metastatic retropharyngeal nodes (RPNs). Methods: IVIM DWI using 14 b-values was performed on RPNs of 30 patients with newly diagnosed metastatic nasopharyngeal carcinoma (NPC) and 30 patients with elevated plasma Epstein-Barr virus (EBV)-DNA without NPC who were part of an EBV-based NPC screening program. Histogram measurements of the two groups were compared for pure diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion volume fraction (f) and apparent diffusion coefficient (ADC) using the Mann-Whitney U test. Area under the curves (AUCs) of significant measurements were calculated from receiver-operating characteristics analysis and compared using the DeLong test. Results: Compared with metastatic RPNs, benign RPNs had lower ADCmean (0.73 vs 0.82 × 10−3 mm2/s) and Dmean (0.60 vs 0.71 × 10−3 mm2/s) and a higher D*mean (35.21 vs 28.66 × 10−3 mm2/s) (all p < 0.05). There was no difference in the f measurements between the two groups (p = 0.204 to 0.301). Dmean achieved the highest AUC of 0.800, but this was not statistically better than the AUCs of the other parameters (p = 0.148 to 0.991). Conclusion: Benign RPNs in patients with EBV-DNA showed greater restriction of diffusion compared with malignant metastatic RPNs from NPC. IVIM did not show a significant advantage over conventional DWI in discriminating benign and malignant nodes. [ABSTRACT FROM AUTHOR]

Germinotropic lymphoproliferative disorder is a rare and rather enigmatic novel entity with distinctive clinicopathological features, one of which is the typical co-infection by Human herpesvirus 8 and Epstein-Barr virus. Human herpesvirus 8 is a lymphotropic virus detected in Kaposi sarcoma, multicentric Castleman disease, primary effusion lymphoma, Human herpesvirus 8-positive diffuse large B cell lymphoma not otherwise specified, and germinotropic lymphoproliferative disorder. Co-infection by Human herpesvirus 8 and Epstein-Barr virus is identified only in two lymphoproliferative diseases: germinotropic lymphoproliferative disorder and primary effusion lymphoma, which are otherwise diseases with totally different clinical presentations and outcomes. Unlike primary effusion lymphoma mostly occurring in immunocompromised individuals and following an aggressive course, germinotropic lymphoproliferative disorder usually presents with single or multiple lymphadenopathy affecting mainly immunocompetent individuals and mostly follows an indolent course. Based on the PRISMA guidelines, we carried out a systematic search on PubMed/MEDLINE, Web of Science, Scopus, EMBASE, and Cochrane Library using the search terms "germinotropic" and "lymphoproliferative disorder." Current scientific literature reports just 19 cases of germinotropic lymphoproliferative disorder. The purpose of our systematic review is to improve our understanding of the disease, focusing on epidemiology, clinical presentation, pathological features, treatment, and outcome. In addition, we discuss the differential diagnosis with the other Human herpesvirus 8-related lymphoproliferative diseases as currently recognized in the World Health Organization classification, adding a focus on lymphoproliferative disorders showing overlapping features. [ABSTRACT FROM AUTHOR]

Objective: A number of studies have recently suggested Epstein-Barr virus (EBV) involvement in the pathogenesis of periodontitis. In this study, we investigated the association between major periodontopathic bacteria Porphyromonas gingivalis ( P. gingivalis) and EBV in Japanese chronic periodontitis (CP) patients. Materials and methods: A group of 25 patients with CP participated in the study along with 13 individuals without periodontitis. Subgingival samples were obtained with paper points. Quantitative real-time polymerase chain reaction (PCR) was used to detect EBV DNA and P. gingivalis. Results: In the CP patients, EBV DNA and P. gingivalis were detected in both 80 % of sites with probing pocket depths (PPD) of ≥5 mm and in 40 and 36 % of sites with PPD ≤3 mm, respectively. EBV DNA and P. gingivalis were detected in 50 and 27 % of the sites in periodontally healthy individuals. Coexistence of EBV DNA and P. gingivalis was significantly higher in the deeper PPD sites of CP patients (68 %) than in the PPD sites of the healthy controls (15 %) and shallow PPD sites of CP patients (12 %). PCR-positive deeper PPD sites of CP patients for EBV DNA and P. gingivalis range between 3.74 × 10∼2.83 × 10 and 2.73 × 10∼6.65 × 10 (copies/ml), respectively. Conclusion: These results suggest an association between EBV DNA, P. gingivalis, and CP in Japanese individuals. Further studies are required to clarify this association; however, we believe that our enhanced understanding of the pathogenesis of periodontal diseases involving viral infections will lead to new treatments. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) infection has been causally associated with occurrence of many malignant neoplasms. EBV-encoded small RNAs (EBERs) have been detected from about 10% of gastric carcinoma tissue cells, suggesting that EBV infection is associated with the development of gastric carcinoma. The present study pooled the data from the papers concerning EBV-related gastric cancers and performed a meta-analysis of 22 research papers. Among these papers, a total of 5475 cases with gastric cancer were enrolled, of whom 411 cases were found EBV-positive, with the EBV-positive rate being 7.5%. Among the EBV-positive gastric cancer cases, the detection rate was 11.1% in males and 3.0% in females. Compared with EBV-negative gastric cancer, EBV-positive gastric cancer had less lymph node metastasis. Based on the histological typing, of the EBV-positive gastric cancers, the diffuse type was 8.1%, and intestinal type was 8.0%. The examined specimen types included stored paraffin blocks and fresh surgically removed specimens, their EBV positive rates were 7.9% and 6.5% respectively. In terms of geographical distribution, the detection rate of EBV-positive gastric cancer was 9.4% in America, 6.1% in Asia and 9.1% in Europe. Meta-analysis showed that EBV infection occurred only in gastric cancer tissue cells and was significantly associated with the patients' gender, lymph node metastases, and the location where tumor tissue generated and geographical distribution ( P<0.05), but was not significantly associated with the patients' histological types of tumor and the types of specimens ( P>0.05). These results suggested that EBV-positive gastric cancer has distinct clinicopathological features. [ABSTRACT FROM AUTHOR]

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

It is unclear whether smoking interacts with different aspects of Epstein–Barr virus (EBV) infection with regard to multiple sclerosis (MS) risk. We aimed to investigate whether smoking acts synergistically with elevated EBNA-1 antibody levels or infectious mononucleosis (IM) history regarding MS risk. Two Swedish population-based case–control studies were used (6,340 cases and 6,219 matched controls). Subjects with different smoking, EBNA-1 and IM status were compared regarding MS risk, by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP). Current and past smokers had higher EBNA-1 antibody levels than never smokers (p < 0.0001). There was an additive interaction between current smoking and high EBNA-1 antibody levels (AP 0.3, 95% CI 0.2–0.4), but not between past smoking and high EBNA-1 antibody levels (AP 0.01, 95% CI − 0.1 to 0.1), with regard to MS risk. An interaction also occurred between current smoking and IM history (AP 0.2, 95% CI 0.004–0.4), but not between past smoking and IM history (AP − 0.06, 95% CI − 0.4 to 0.3). Current smoking increases EBNA-1 antibody levels and acts synergistically with both aspects of EBV infection to increase MS risk, indicating that there is at least one pathway to disease in which both risk factors are involved. [ABSTRACT FROM AUTHOR]