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The article comments on a paper by M. A. Pule and colleagues about a strategy for T cell immunotherapy that takes advantage of the sustained immune response. According to the author, the strategy comes from the unique interactions of Epstein-Barr virus with the immune system. He adds that retroviral vectors encoding a tumor-specific chimeric antigen receptor (CAR) consisting of an antibody-derived single-chain variable fragment and an intracellular CD3 domain were used.

Epstein-Barr virus (EBV) reactivation is common in sepsis patients but the extent and nature of this remains unresolved. We sought to determine the incidence and correlates of EBV-positivity in a large sepsis cohort. We also hypothesised that EBV reactivation would be increased in patients in whom relative immunosuppression was the major feature of their sepsis response. To identify such patients we aimed to use knowledge of sepsis response subphenotypes based on transcriptomic studies of circulating leukocytes, specifically patients with a Sepsis Response Signature endotype (SRS1) that we have previously shown to be associated with increased mortality and features of immunosuppression. We assayed EBV from the plasma of intensive care unit (ICU) patients with sepsis due to community-acquired pneumonia. In total 730 patients were evaluated by targeted metagenomics (n = 573 patients), digital droplet PCR (n = 565), or both (n = 408). We had previously analysed gene expression in peripheral blood leukocytes for a subset of individuals (n = 390). We observed a 37% incidence of EBV-positivity. EBV reactivation was associated with longer ICU stay (12.9 vs 9.2 days; p = 0.004) and increased organ failure (day 1 SOFA score 6.9 vs 5.9; p = 0.00011). EBV reactivation was associated with the relatively immunosuppressed SRS1 endotype (p = 0.014) and differential expression of a small number of biologically relevant genes. These findings are consistent with the hypothesis that viral reactivation in sepsis is a consequence of immune compromise and is associated with increasing severity of illness although further mechanistic studies are required to definitively illustrate cause and effect. [ABSTRACT FROM AUTHOR]

The Epstein-Barr virus (EBV) establishes lifelong infections in > 90% of the human population. Although contained as asymptomatic infection by the immune system in most individuals, EBV is associated with the pathogenesis of approximately 1.5% of all cancers in humans. Some of these EBV-associated tumors have been successfully treated by the infusion of virus-specific T-cell lines. Recent sequence analyses of a large number of viral isolates suggested that distinct EBV strains have evolved in different parts of the world. Here, we assessed the impact of such sequence variations on EBV-specific T-cell immunity. With the exceptions of EBNA2 and the EBNA3 family of proteins, an overall low protein sequence disparity of about 1% was noted between Asian viral isolates, including the newly characterized M81 strain, and the prototypic EBV type 1 and type 2 strains. However, when T-cell epitopes including their flanking regions were compared, a substantial proportion was found to be polymorphic in different EBV strains. Importantly, CD4+ and CD8+ T-cell clones specific for viral epitopes from one strain often showed diminished recognition of the corresponding epitopes in other strains. In addition, T-cell recognition of a conserved epitope was affected by amino acid exchanges within the epitope flanking region. Moreover, the CD8+ T-cell response against polymorphic epitopes varied between donors and often ignored antigen variants. These results demonstrate that viral strain heterogeneity may impair antiviral T-cell immunity and suggest that immunotherapeutic approaches against EBV should preferably target broad sets of conserved epitopes including their flanking regions. [ABSTRACT FROM AUTHOR]

Background:Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) up-regulates the human leukocyte antigen (HLA) class I antigen presentation machinery (APM). This appears counterintuitive with immune evasion in EBV-associated tumours like nasopharyngeal carcinoma (NPC).Methods:Latent membrane protein 1-transfected epithelial cell lines were used as a model system to study the impact of LMP1 and c-Myc on HLA class I components. The expression of components of the HLA class I APM, c-Myc and Ki-67 was analysed in LMP1+ and LMP1− NPC by immunohistochemistry.Results:In epithelial cells, LMP1 up-regulated HLA class I APM. This effect could be counteracted by c-Myc, which itself was up-regulated by LMP1 apparently through IL6 induction and Jak3/STAT3 activation. Studies of NPC biopsies revealed down-regulation of HLA class I APM expression. No difference was observed between LMP1+ and LMP1− NPC. However, expression of Ki-67 and c-Myc were up-regulated in LMP1+ tumours.Conclusion:These findings raise the possibility that c-Myc activation in NPC might antagonise the effect of LMP1 on HLA class I expression thus contributing to immune escape of tumour cells. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) infection, history of infectious mononucleosis (IM) and HLA-A and DRB1 have all been proposed as risk factors for multiple sclerosis (MS). Our aim was to analyse possible interactions between antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA1) or EBNA1 fragments, presence of DRB1*15 and absence of A*02. The study population includes newly diagnosed cases and matched controls. Interaction on the additive scale was calculated using attributable proportion due to interaction (AP), which is the proportion of the incidence among individuals exposed to two interacting factors that is attributable to the interaction per se. IM showed association with MS, odds ratio (OR)=1.89 (1.45-2.48% confidence interval (CI)), as did raised EBNA1 IgG OR=1.74 (1.38-2.18 95%CI). All EBNA1 fragment IgGs were associated with MS risk. However, EBNA1 fragment 385-420 IgG levels were more strongly associated to MS than total EBNA1 IgG, OR=3.60 (2.75-4.72 95%CI), and also interacted with both DRB1*15 and absence of A*02, AP 0.60 (0.45-0.76 95%CI) and AP 0.39 (0.18-0.61 95%CI), respectively. The observed interaction between HLA class I and II genotype and reactivity to EBV-related epitopes suggest that the mechanism through which HLA genes influence the risk of MS may, at least in part, involve the immune control of EBV infection. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) with onset in childhood offers a unique opportunity to study the infectious background of this disease but the immune reactions against infectious agents in such children have only recently been investigated. These and other epidemiological studies strongly implicate involvement of one or more infectious agents in the aetiology of MS, with Epstein-Barr virus (EBV) being the prime candidate. Rather than being the actual cause of MS, it is more probable that these agents are involved in the development of immunoregulatory pathways. These pathways, if disturbed by hygiene-related factors including an altered sequence of infections, may generate and maintain a deficit within the immunological network that facilitates, to particular early events in the development of MS, preceding the onset of MS disease by years or a decade. A framework that can serve as a guide for further epidemiological, immunologic and molecular biologic investigations is formulated. This approach may shed light on the complex natural history of MS and may lead to rational preventive and therapeutic strategies. It is possible that, in the future, MS could be prevented by vaccination against EBV in early childhood; the framework is of relevance to the design of an appropriate type of vaccine. [ABSTRACT FROM AUTHOR]