Inhibition of antigen processing by the internal repeat region of the Epstein–Barr virus nuclear antigen-1

Levitskaya, Jelena; Coram, Michael; Levitsky, Victor; Imreh, Stefan; Steigerwald-Mullen, Patty M.; Klein, George; Kurilla, Michael G.; Masucci, Maria G.

doi:10.1038/375685a0

Cited by 736 publications

(489 citation statements)

References 26 publications

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“…Unlike the latency III pattern observed in EBV-related lymphoproliferative disorders in patients with immunodeficiency (Hamilton-Dutoit et al, 1993), NK/T-cell lymphomas may minimize the expression of the latency-associated viral antigens which might be targeted by host immune system. EBNA-1 is constantly expressed by EBV-infected cells in any latency pattern, but the host's immune response never occurs against the molecules (Levitskaya et al, 1995). LMP-1 acts as a direct oncogene to transform epithelial cells morphologically (Fahraeus et al, 1990) and prevent B-lymphoma cells from undergoing apoptosis by up-regulating the expression of cellular bcl-2 (Henderson et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

The latency pattern of Epstein–Barr virus infection and viral IL-10 expression in cutaneous natural killer/T-cell lymphomas

Iwatsuki

Oyama

et al. 2001

Br J Cancer

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SummaryThe nasal type, extranodal natural killer or T(NK/T)-cell lymphoma is usually associated with latent Epstein-Barr virus (EBV) infection. In order to elucidate the EBV gene expression patterns in vivo, we examined eight patients with cutaneous EBV-related NK/T-cell lymphomas, including six patients with a NK-cell phenotype and two patients with a T-cell phenotype. The implication of EBV in the skin lesions was determined by the presence of EBV-DNA, EBV-encoded nuclear RNA (EBER) and a clonality of EBV-DNA fragments containing the terminal repeats. Transcripts of EBV-encoded genes were screened by reverse transcription-polymerase chain reaction (RT-PCR), and confirmed by Southern blot hybridization. The expression of EBV-related antigens was examined by immunostaining using paraffinembedded tissue sections and cell pellets of EBV-positive cell lines. Our study demonstrated that all samples from the patients contained EBV nuclear antigen (EBNA)-1 mRNA which was transcribed using the Q promoter, whereas both the Q promoter and another upstream promoter (Cp/Wp) were used in EBV-positive cell lines, B95.8, Raji and Jiyoye. Latent membrane protein-1 (LMP-1) mRNA was detected in seven of eight patients and all cell lines, whereas EBNA-2 transcripts were found only in the cell lines. Immunostaining showed no LMP-1, EBNA-2 or ZEBRA antigens in the paraffin-embedded tissue sections, although they were positive in the cell line cells. Latent BHRF1 transcripts encoding bcl-2 homologue and BCRF1 transcripts encoding viral interleukin (vIL)-10 were detected in one and two of eight patients, respectively. A patient with NK-cell lymphoma expressing both transcripts died of rapid progression of the illness. Our results indicate that the restricted expression of the latency-associated EBV genes and the production of vIL-10 and bcl-2 homologue may favour tumour growth, evading the host immune surveillance.

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Section: Discussionmentioning

confidence: 99%

The latency pattern of Epstein–Barr virus infection and viral IL-10 expression in cutaneous natural killer/T-cell lymphomas

Iwatsuki

Oyama

et al. 2001

Br J Cancer

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“…EBNA-1 is an immunodominant latent target of EBVspecific CD4 1 T cells [19,20]. Although it has been described in the past to escape from recognition by CD8 1 T cells due to Gly/Ala repeated domains preventing proteasome-dependent processing for presentation on MHC class I [21], more recent studies revealed the existence of EBNA-1-specific CD8 1 T cells [15,22,23]. Moreover, detection of anti-EBNA IgG in seropositive individuals suggests need for CD4 help.…”

Section: Introductionmentioning

confidence: 99%

Human peripheral blood and bone marrow Epstein–Barr virus‐specific T‐cell repertoire in latent infection reveals distinct memory T‐cell subsets

Guerreiro

Letsch

et al. 2010

Eur J Immunol

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EBV infection leads to life-long viral persistence. Although EBV infection can result in chronic disease and malignant transformation, most carriers remain disease-free as a result of effective control by T cells. EBV-specific IFN-c-producing T cells could be demonstrated in acute and chronic infection as well as during latency. Recent studies, however, provide evidence that assessing IFN-c alone is insufficient to assess the quantity and quality of a T-cell response. Using overlapping peptide pools of latent EBV nuclear antigen 1 and lytic BZLF-1 protein and multicolor flow cytometry, we demonstrate that the majority of ex vivo EBV-reactive T cells in healthy virus carriers are indeed IL-2-and/or TNF-producing memory cells, the latter being significantly more frequent in BM. After in vitro expansion, a substantial number of EBV-specific CD4 1 and CD8 1 T cells retained a CC-chemokine receptor 7 (CCR7)-positive memory phenotype. Based on their cytokine profiles, six different EBV-specific T-cell subsets could be distinguished with TNF-single or TNF/IL-2-double producing cells expressing the highest CCR7 levels resembling earlydifferentiated memory T cells. Our study delineates the memory T-cell profile of a protective immune response and provides a basis for analyzing T-cell responses in EBVassociated diseases.Key words: BM . EBV . Immune monitoring . Multifunctional T cells . T-cell memory IntroductionEBV is a human gamma herpesvirus that is widespread in all human populations. Following oral transmission, EBV replicates in the oropharyngeal epithelial cells and infects mucosal B cells, leading to a life-long persistence in the memory B-cell pool [1,2]. The primary infection occurs usually during childhood and is often asymptomatic; however, infection is manifested as acute infectious mononucleosis in a subset of patients [3]. Despite the relatively benign course in most carriers, EBV reactivation is considered as a risk-factor both for malignant transformation and autoimmune diseases. The ability of the EBV encoded protein 1566LMP-1 to induce T-cell-independent immunoglobulin class switch DNA recombination and BAFF, a B-cell activating factor, that rescues self-reactive T cells, is considered to play an important role in the pathogenesis of EBV-related autoimmune and lymphoproliferative disease [4]. EBV is causatively linked to nasopharyngeal carcinoma and B-cell malignant diseases such as endemic Burkitt's lymphoma, Hodgkin's lymphoma and posttransplant lymphoproliferative diseases (PTLD) [5][6][7]. Recent data suggest that EBV is associated with various autoimmune diseases as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and primary Sjögren's syndrome [8,9]. Chronic active EBV infection can also cause Chronic Fatigue Syndrome, which is frequently associated with autoimmune thyreoiditis [10].The EBV cycle has two distinct stages, the latent infection where the genome is maintained at a constant copy number per cell and limited regions of the genome are expressed and the lytic cycle w...

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“…CTLs specific for BARF0 were unable to recognize cells expressing the antigen at low levels, 18 EBNA1 is not processed for HLA class I presentation 13 and LMP1 is frequently mutated. 16 Although LMP2B-specific CTLs have been reported, this protein lacks a significant portion of the LMP2A protein that likely contains important CTL epitopes.…”

Section: Discussionmentioning

confidence: 99%

“…EBNA1 is not processed for HLA class I presentation due to an internal glycine-alanine repeat region. 13 LMP1-specific CTL clones are rare in EBV ϩ donors, 14 and very few LMP1 epitopes have been identified. 15 Moreover, LMP1 displays heterogeneity between viral strains, 16 and CTLs raised against B cell (B95-8 prototype) derived LMP1 may not recognize LMP1 tumor variants.…”

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confidence: 99%

Adenoviral gene transfer into dendritic cells efficiently amplifies the immune response to LMP2A antigen: A potential treatment strategy for Epstein-Barr virus-positive Hodgkin's lymphoma

et al. 2001

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Improvements in radiochemotherapy have correspondingly improved the prognosis of patients with HodgkinЈs lymphoma. 1 However, patients resistant to the standard therapeutic approaches have a poor outcome. Moreover, both life expectancy and quality of life of patients cured of Hodgkin's lymphoma are significantly reduced by treatment-related mortality and morbidity. 2,3 These limitations of current treatment protocols illustrate the need for more effective and less toxic therapeutic approaches.In HodgkinЈs lymphomas, up to 49% of specimens have been shown to carry EBV DNA and to express EBV genes. 4,5 Adoptive immunotherapy with donor-derived, EBV-specific CTLs has significantly improved the clinical outcome of patients with EBV ϩ immunoblastic lymphoma after T cell-depleted allogeneic stemcell transplantation. 6,7 In an ongoing study, our group has successfully generated EBV-specific CTLs in patients with EBV ϩ Hodgkin's lymphoma. 8 After infusion, these CTLs home to the tumor sites, persist in the circulation for up to 9 months and produce transient clinical benefits. In this protocol, LCLs are used as EBV antigen-presenting cells. LCLs activate polyclonal CTL populations that are preferentially directed against the immunodominant EBNA3A, -3B and -3C EBV proteins. 9 These immunogenic proteins are not expressed in HRS cells. Instead, the EBV antigens on HRS cells are restricted to the expression of a subset of latent proteins, EBNA1, LMP1, LMP2A and BARF0. 10 -12 LCLs have limited efficacy at stimulating CTLs directed against these subdominant proteins.Targeting the EBV proteins expressed in EBV ϩ HRS cells is further complicated by their limited immunogenicity. EBNA1 is not processed for HLA class I presentation due to an internal glycine-alanine repeat region. 13 LMP1-specific CTL clones are rare in EBV ϩ donors, 14 and very few LMP1 epitopes have been identified. 15 Moreover, LMP1 displays heterogeneity between viral strains, 16 and CTLs raised against B cell (B95-8 prototype) derived LMP1 may not recognize LMP1 tumor variants. 17 BARF0 is a protein expressed from the BamHI A rightward transcript. Attempts to identify BARF0-specific CTLs have produced lymphocytes that recognized target cells expressing BARF0 at high levels but failed to recognize the antigen expressed at lower levels in LCLs. 18 LMP2A epitopes were shown to be conserved among Hodgkin's lymphoma biopsy samples displaying little heterogeneity between viral strains. 19,20 Also, most donors have a low but measurable frequency of circulating LMP2A-specific CTLs that can be activated and expanded in vitro. 14 Hence, LMP2A may be the protein of choice to be targeted by CTLs in patients with Hodgkin's lymphoma.To stimulate LMP2A-specific CTLs, LMP2A peptide-pulsed DCs have been successfully used, but this approach is limited to known MHC-restricted peptides. 21,22 A more promising strategy is the production of CTLs by genetically modified DCs that direct the CTL response to virally transduced genes. [23][24][25] This approach allows expression of t...

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Inhibition of antigen processing by the internal repeat region of the Epstein–Barr virus nuclear antigen-1

Cited by 736 publications

References 26 publications

The latency pattern of Epstein–Barr virus infection and viral IL-10 expression in cutaneous natural killer/T-cell lymphomas

The latency pattern of Epstein–Barr virus infection and viral IL-10 expression in cutaneous natural killer/T-cell lymphomas

Human peripheral blood and bone marrow Epstein–Barr virus‐specific T‐cell repertoire in latent infection reveals distinct memory T‐cell subsets

Adenoviral gene transfer into dendritic cells efficiently amplifies the immune response to LMP2A antigen: A potential treatment strategy for Epstein-Barr virus-positive Hodgkin's lymphoma

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