The c-myc oncogene stimulates ribosomal biogenesis and protein synthesis to promote cellular growth. However, the pathway by which cells sense and restore dysfunctional mRNA translation and how this is linked to cell proliferation and growth is not known. We here show that mRNA translation stress in cis triggered by the gly-ala repeat sequence of Epstein-Barr virus (EBV)-encoded EBNA1, results in PI3Kδ-dependent induction of E2F1 mRNA translation with the consequent activation of c-Myc and cell proliferation. Treatment with a specific PI3Kδ inhibitor Idelalisib (CAL-101) suppresses E2F1 and c-Myc levels and causes cell death in EBNA1-induced B cell lymphomas. Suppression of PI3Kδ prevents E2F1 activation also in non-EBV-infected cells. These data illustrate an mRNA translation stress-response pathway for E2F1 activation that is exploited by EBV to promote cell growth and proliferation, offering new strategies to treat EBV-carrying cancers.

• MeSH
• buněčné linie MeSH
• fosfatidylinositol-3-kinasy třídy I genetika   metabolismus   MeSH
• interakce hostitele a patogenu genetika   MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory genetika   patologie   virologie   MeSH
• proliferace buněk genetika   MeSH
• proteosyntéza * MeSH
• regulace genové exprese u nádorů MeSH
• transkripční faktor E2F1 genetika   metabolismus   MeSH
• virus Epsteinův-Barrové - jaderné antigeny genetika   metabolismus   MeSH
• virus Epsteinův-Barrové genetika   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Adoptive transfer of multivirus-specific T cell lines (MVST) is an advanced tool for immunotherapy of virus infections after hematopoietic stem cell transplantation (HSCT). Their preparation includes activation of donor virus-specific T cells by the mixture of oligopeptides derived from immunodominant antigens of several most harmful viruses, i.e. human cytomegalovirus (HCMV), polyomavirus BK (BKV), Epstein-Barr virus (EBV) and adenovirus (ADV). The aim of our study was to find out whether antigenic competition may have an impact on the expansion of virus-specific T cells. MVST from several heathy blood donors were generated using a pulse of overlapping oligopeptides (PepMixes™, derived from the IE1 and pp65 CMV antigens, VP1 and LTAG BKV antigens, BZLF1 and EBNA1 proteins of EBV and hexon protein from ADV) and short time culture in the presence of IL-7 and IL-4. The amount of virus-specific T cells in MVST was measured by ELISPOT and flow cytometry after re-stimulation with individual antigens. To evaluate antigenic competition, MVST were expanded either with a complete set of antigens or with the mixture lacking some of them. MVST expanded with the antigen mixture including CMV antigens contained a lower proportion of the T cells of other antigen specificities. A similar inhibitory effect was not apparent for EBV-derived peptides. The competitive effect of CMV antigens was most pronounced in MVST from CMV-seropositive donors and was mediated by both IE1 and pp65-derived peptides. Antigenic competition did not influence the phenotype of either CMV- or BKV-specific T cells. Both T cell populations had an effector memory phenotype (CD45RO+, CD27-, CCR7-). However, CMV-specific T cells preferentially consist of CD8+ while in BKV-specific T cells, the CD4+ phenotype predominated. Modification of the MVST manufacture protocol to prevent antigenic competition may increase the efficacy of MVST in therapy of BKV infections in HSCT recipients.

• MeSH
• Adenoviridae imunologie   patogenita   MeSH
• adenovirové infekce lidí imunologie   terapie   virologie   MeSH
• aktivace lymfocytů MeSH
• antigeny virové imunologie   MeSH
• cytomegalovirové infekce imunologie   terapie   virologie   MeSH
• Cytomegalovirus imunologie   patogenita   MeSH
• fenotyp MeSH
• imunodominantní epitopy MeSH
• imunoterapie adoptivní * MeSH
• infekce onkogenními viry imunologie   terapie   virologie   MeSH
• infekce virem Epsteina-Barrové imunologie   terapie   virologie   MeSH
• interakce hostitele a patogenu MeSH
• kultivované buňky MeSH
• lidé MeSH
• polyomavirové infekce imunologie   terapie   virologie   MeSH
• T-lymfocyty imunologie   transplantace   virologie   MeSH
• transplantace hematopoetických kmenových buněk škodlivé účinky   MeSH
• virové nemoci imunologie   terapie   virologie   MeSH
• virus BK imunologie   patogenita   MeSH
• virus Epsteinův-Barrové imunologie   patogenita   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The Epstein-Barr virus (EBV) is found almost exclusively in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), yet its contribution to this tumour remains poorly understood. We have focused on the EBV-encoded latent membrane protein-1 (LMP1), a constitutively activated CD40 homologue expressed in almost all EBV-positive DLBCLs and which can disrupt germinal centre (GC) formation and drive lymphomagenesis in mice. Comparison of the transcriptional changes that follow LMP1 expression with those that follow transient CD40 signalling in human GC B cells enabled us to define pathogenic targets of LMP1 aberrantly expressed in ABC-DLBCL. These included the down-regulation of S1PR2, a sphingosine-1-phosphate (S1P) receptor that is transcriptionally down-regulated in ABC-DLBCL, and when genetically ablated leads to DLBCL in mice. Consistent with this, we found that LMP1-expressing primary ABC-DLBCLs were significantly more likely to lack S1PR2 expression than were LMP1-negative tumours. Furthermore, we showed that the down-regulation of S1PR2 by LMP1 drives a signalling loop leading to constitutive activation of the phosphatidylinositol-3-kinase (PI3-K) pathway. Finally, core LMP1-PI3-K targets were enriched for lymphoma-related transcription factors and genes associated with shorter overall survival in patients with ABC-DLBCL. Our data identify a novel function for LMP1 in aggressive DLBCL. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

• MeSH
• 1-fosfatidylinositol-3-kinasa metabolismus   MeSH
• antigeny CD40 genetika   metabolismus   MeSH
• databáze genetické MeSH
• difúzní velkobuněčný B-lymfom genetika   metabolismus   mortalita   virologie   MeSH
• infekce virem Epsteina-Barrové mortalita   virologie   MeSH
• interakce hostitele a patogenu MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• prognóza MeSH
• proteiny virové matrix genetika   metabolismus   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• receptory sfingosin-1-fosfátu genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• signální transdukce MeSH
• virová transformace buněk MeSH
• virus Epsteinův-Barrové genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The oncogenic Epstein-Barr virus (EBV) evades the immune system but has an Achilles heel: its genome maintenance protein EBNA1. Indeed, EBNA1 is essential for viral genome maintenance but is also highly antigenic. Hence, EBV seemingly evolved a system in which the glycine-alanine repeat (GAr) of EBNA1 limits the translation of its own mRNA to the minimal level to ensure its essential function, thereby, at the same time, minimizing immune recognition. Therefore, defining intervention points at which to interfere with GAr-based inhibition of translation is an important step to trigger an immune response against EBV-carrying cancers. The host protein nucleolin (NCL) plays a critical role in this process via a direct interaction with G-quadruplexes (G4) formed in the GAr-encoding sequence of the viral EBNA1 mRNA. Here we show that the C-terminal arginine-glycine-rich (RGG) motif of NCL is crucial for its role in GAr-based inhibition of translation by mediating interaction of NCL with G4 of EBNA1 mRNA. We also show that this interaction depends on the type I arginine methyltransferase family, notably PRMT1 and PRMT3: drugs or small interfering RNA that target these enzymes prevent efficient binding of NCL on G4 of EBNA1 mRNA and relieve GAr-based inhibition of translation and of antigen presentation. Hence, this work defines type I arginine methyltransferases as therapeutic targets to interfere with EBNA1 and EBV immune evasion.

• MeSH
• imunitní systém metabolismus   MeSH
• infekce onkogenními viry * farmakoterapie   metabolismus   MeSH
• infekce virem Epsteina-Barrové * genetika   MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• onkogenní viry genetika   metabolismus   MeSH
• proteinarginin-N-methyltransferasy MeSH
• represorové proteiny MeSH
• virus Epsteinův-Barrové - jaderné antigeny genetika   metabolismus   MeSH
• virus Epsteinův-Barrové * genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Recent studies have revived interest in the long-scrutinized association between Epstein-Barr virus (EBV) and multiple sclerosis (MS). We review this evidence and discuss it in relation to MS pathological and clinical features and patients' response to immunosuppressive therapies. RECENT FINDINGS: Serological evidence of previous exposure to EBV in children with MS supports a role for EBV infection early in MS pathogenesis, as already indicated by prospective studies in adults. Higher antibody titers and T-cell responses to EBV in patients compared to healthy EBV carriers indicate possible continuous viral reactivation, whereas there is some evidence that EBV could break immune tolerance to myelin antigens through molecular mimicry. Detection of EBV-infected B-cells in patients' brain raises the possibility that intrathecal B-cell abnormalities and T-cell-mediated immunopathology in MS are the consequence of a persistently dysregulated EBV infection. Accordingly, targeting T-cells and/or B-cells with monoclonal antibody therapies ameliorates MS. Whether EBV has a causative or pathogenic role in MS can now be addressed in relation to genetic, hormonal and other environmental influences that may affect EBV-host interactions. SUMMARY: By shedding light on the involvement of EBV in MS, these findings will pave the way to disease prevention and increase the therapeutic index of future treatments.

• MeSH
• B-lymfocyty imunologie   virologie   MeSH
• financování organizované MeSH
• genetická predispozice k nemoci MeSH
• imunoglobulin G biosyntéza   imunologie   MeSH
• imunosupresiva terapeutické užití   MeSH
• infekce virem Epsteina-Barrové farmakoterapie   imunologie   MeSH
• lidé MeSH
• mozek imunologie   patologie   MeSH
• recidiva MeSH
• roztroušená skleróza farmakoterapie   imunologie   patologie   virologie   MeSH
• těhotenství MeSH
• virus Epsteinův-Barrové imunologie   MeSH
• zánět imunologie   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• Hodgkinova nemoc patofyziologie   terapie   MeSH
• Publikační typ
• sborníky MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• hematologie a transfuzní lékařství