180,668 research outputs found
Clonal origin of Epstein-Barr virus-infected T/NK-cell subpopulations in chronic active Epstein-Barr virus infection
No full textClonal expansion of Epstein-Barr virus (EBV) infected B-cells occasionally occurs in immunocompromized subjects. EBV-infected T/natural killer (NK)-cells proliferate in patients with chronic active EBV infection (CAEBV) that is a rare mononucleosis syndrome. It is classified into either T-cell type or NK-cell type according to the primary target of infection, while the pathogenesis remains unclear. To search the clonal origin of EBV-infected T/NK-cells, virus distribution and clonotype were assessed by using highly purified cell fractions obtained from 6 patients. Patient 1 had a monoclonal proliferation of EBV-infected T-cell receptor Vδ2/Vγ9-expressing cells, and carried lower copy number of EBV in αβT-cells. Patients 2 and 3 had a clonal expansion of EBV-infected CD4+T-cells, and lower EBV load in CD56+cells. Patients 4, 5 and 6 had an expansion of CD56+cells with higher EBV load than CD3+cells. EBV-terminal repeats were determined as clonal bands in the minor targeted populations of 5 patients. The size of terminal repeats indicated the same clonotype in minor subsets as in major subsets of 4 patients. However, EBV was not detected in bone marrow-derived lineage negative CD34+cells of patients. These results suggested that EBV could infect T/NK-cells at differentiation stage, but spared bone marrow CD34+hematopoietic stem cells in CAEBV patients
Carving a legacy : the identity of Jacob Epstein (1880-1959)
No full textThe purpose of this thesis is to examine the efforts which were made during the life of Jacob Epstein and at the time his death to fix a particular identity that has thus shaped his legacy. The question that this thesis wishes to address is: how was Jacob Epstein's legacy carved?
The first part of this thesis, entitled 'Remembering Epstein', seeks to unpack and examine the written discourse surrounding his death. This will be done by assessing the themes, debates and considerations of Epstein's position in the history of art and will focus on four case studies: the obituaries and memorial pieces that were written immediately after Epstein's death; a memorial service that was held at St. Paul's Cathedral; a failed proposal
to tum Epstein's home studio into a museum; and the organisation and critical reception of the Epstein Memorial Exhibition held in Edinburgh in 1961. The second part of this thesis, entitled 'Writing a Legacy', attends to the analysis of texts which were written about or by Epstein throughout his career. This will be done through a close examination of those texts which have come to shape our understanding of Epstein's place in the history of art and will focus on five case studies: the writings of T. E. Hulme; Epstein by Bernard Van Dieren; a series of interviews with Epstein by Arnold Haskell, entitled The Sculptor Speaks; Epstein's role in protesting against repairs to ancient sculpture in the British Museum; and a chapter entitled 'My Place in Sculpture' from the 1954 edition of Epstein's autobiography. The final part of the thesis, entitled 'Selected Works', will focus on six separate sculptures as case studies for assessing different aspects of Epstein's artistic output. The works which
will be examined: The Rock Drill (1913), The Risen Christ (1917-19), Madonna and Child (1926-27), Genesis (1929), Albert Einstein (1933), and Madonna and Child (1950-52)
Relationship Between Non-Hodgkin's Lymphoma and Blood Levels of Epstein-Barr Virus in Children in North-Western Tanzania: A Case Control Study.
No full textNon-Hodgkin's Lymphomas (NHL) are common in African children, with endemic Burkitt's lymphoma (BL) being the most common subtype. While the role of Epstein-Barr Virus (EBV) in endemic BL is known, no data are available about clinical presentations of NHL subtypes and their relationship to Human Immunodeficiency Virus (HIV) infection and Epstein Barr Virus (EBV) load in peripheral blood of children in north-western, Tanzania. A matched case control study of NHL subtypes was performed in children under 15 years of age and their respective controls admitted to Bugando Medical Centre, Sengerema and Shirati district designated hospitals in north-western, Tanzania, between September 2010 and April 2011. Peripheral blood samples were collected on Whatman 903 filter papers and EBV DNA levels were estimated by multiplex real-time PCR. Clinical and laboratory data were collected using a structured data collection tool and analysed using chi-square, Fisher and Wilcoxon rank sum tests where appropriate. The association between NHL and detection of EBV in peripheral blood was assessed using conditional logistic regression model and presented as odds ratios (OR) and 95% confidence intervals (CI). A total of 35 NHL cases and 70 controls matched for age and sex were enrolled. Of NHLs, 32 had BL with equal distribution between jaw and abdominal tumour, 2 had large B cell lymphoma (DLBCL) and 1 had NHL-not otherwise specified (NHL-NOS). Central nervous system (CNS) presentation occurred only in 1 BL patient; 19 NHLs had stage I and II of disease. Only 1 NHL was found to be HIV-seropositive. Twenty-one of 35 (60%) NHL and 21 of 70 (30%) controls had detectable EBV in peripheral blood (OR = 4.77, 95% CI 1.71 - 13.33, p = 0.003). In addition, levels of EBV in blood were significantly higher in NHL cases than in controls (p = 0.024). BL is the most common childhood NHL subtype in north-western Tanzania. NHLs are not associated with HIV infection, but are strongly associated with EBV load in peripheral blood. The findings suggest that high levels of EBV in blood might have diagnostic and prognostic relevance in African children
Epstein-Barr virus latency in vivo and in vitro
No full textIn this thesis, I studied 1) The latency situation of Epstein- Barr virus (EBV) in bone marrow transplanted (BMT) patients and healthy virus carriers. 2) The role of EBNA1 and cellular transcriptional factors Oct and Grg/TLE family in EBV latency switch.B lymphocytes have been identified as the main reservoir of latent Epstein-Barr virus (EBV) in healthy virus carriers. We have established a semi-quantitative PCR method (SQ-PCR) to estimate the EBV genome load in the blood B-cell subpopulation in healthy individuals. EBV DNA was detected in subfractionated IgM-, IgG- and IgA-positive B cells. Between 80%. and 90% of the viral DNA was found in the lgA-positive compared with the lgA-negative fraction.We used SQ-PCR to monitor the blood levels of EBV-DNA in 9 patients receiving allogeneic BMT. Four of 5 recipients of HLA-mismatched T-cell-depleted grafts showed a 4- to 5-log increase of EBV-DNA within 1 to 3 months after BMT. Administration of 2 to 4 infusions of 107 EBV-specific cytotoxic T-lymphocytes (CTLs)/M2 starting from the time of maximal virus load resulted in a 2- to 3-log decrease of virus titers in 3 patients. A moderate increase of virus titers was also detected in 3 of 4 patients receiving unmanipulated HLA-matched grafts, whereas one patient with Wiskott-Aldrich syndrome (WAS) reached a 5-log increase of EBVDNA load within 70 days after BMT. Our results suggest that a rapid increase of circulating EBV-DNA occurs in the absence of EBV-specific T-cell precursors or in the presence of congenital immune defects that prevent the reestablishment of virus-specific immunity. Prophylactic administration of EBV-CTI-s early after 13MT appears to provide the most effective protection against the development of EBV-associated lymphoproliferative disease.We identified that Cp could also can be activated by octamer-binding factor (OCT) proteins. Physical binding to the FR by the cellular transcription factors OCT1 and OCT2 was demonstrated by using electrophoretic mobility shift assay (EMSA). Furthermore, OCT2 alone or OCTI in combination with co-regulator Bob-1could drive transcription of a heterologous thymidine kinase promoter liked to the FR both in B cells and epithelial cells. Cp controlled by the FR also activated by binding of OCT2 to FR. OCT proteins can recruit the Grg/TLE - farmly of transcription factor regulatory proteins (co-factors) and those proteins repress OCT2 promoter activity through FR. Although all Grg/TLE variants could repress the OCT2 induced activity from a FR-luciferase report vector, Grg-3 was most efficient. Grg/TLE proteins did not inhibit the EBNA1 activity on their own but when cotransfected with OCT2 also the EBNA I-induced FR enhancer effect was repressed. Addition of EBNA1 efficiently counteracted the transcriptional repression evoked by OCT-2 and Grg/TLE3. We also demonstrate that the levels of EBNA1 and OCT2 differ dramatically between latency III and I cells.Using competition and base substitutions of oligo-probes in EMSA1 we mapped in detail the binding of OCT-proteins to all octamer sequence three bp away from the EBNA1 core binding site. Different FR repeats vary in their ability to form complexes with OCTI, OCT2 and their cofactors. Direct physical binding of OCT and Grg/TLE to FR repeats was demonstrated in vitro by affinity adsorption with FR specific DNA as bait. Both OCT2 and EBNA I were shown to bind FR in vivo in EBV-positive cells representing latency I or III utilizing Chromatin immunoprecipitation assay (ChIP). Based on our results, a model is suggested that the on-off switch of the EBV C promoter in latency is controlled by competition between EBNA1 and OCT-proteins together with their co regulators.List of scientific papersI. Ehlin-Henriksson B, Zou JZ, Klein G, Ernberg I (1999). Epstein-Barr virus genomes are found predominantly in IgA-positive B cells in the blood of healthy carriers. Int J Cancer. 83(1): 50-4. https://pubmed.ncbi.nlm.nih.gov/10449607II. Gustafsson A, Levitsky V, Zou JZ, Frisan T, Dalianis T, Ljungman P, Ringden O, Winiarski J, Ernberg I, Masucci MG (2000). Epstein-Barr virus (EBV) load in bone marrow transplant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells. Blood. 95(3): 807-14. https://pubmed.ncbi.nlm.nih.gov/10648390III. Almqvist J, Zou JZ, Linderson Y, Borestrom C, Altiok E, Zetterberg H, Rymo L, Pettersson S, Ernberg I (2005). Functional interaction of Oct transcription factors with the family of repeats in Epstein-Barr virus oriP. J Gen Virol. 86(5): 1261-7. https://pubmed.ncbi.nlm.nih.gov/15831936IV. Almqvist J, Zou JZ, Borestrom C, Pettersson S, Rymo L, Ernberg I (2006). Repression of Epstein-Barr virus enhancer Family of Repeats mediated transcription by Oct and Grg/TLE transcriptional regulators, suggests an involvement in switching of latency programs. [Manuscript]V. Zou JZ, Almqvist J, Ernberg I (2006). Characterization of the Oct-protein binding sites in the FR control element of the C promoter and in Q promoter in Epstein-Barr virus (EBV). [Manuscript]</p
Latent Epstein-Barr virus infection and the germinal center reaction
No full textEpstein-Barr virus (EBV) is a γ-herpes virus which preferentially infects human B lymphocytes. It is highly adapted to persist in B cells since it encodes for proteins which mimic several cellular proteins playing an important role in B cell biology. Thus, the viral Latent Membrane Proteins (LMP) 1 and 2A are considered to be functional homologues of the CD40 receptor and the B cell receptor, respectively. It has been postulated that EBV uses the normal T cell dependent immune response B cell differentiation pathway (the so-called germinal center reaction) for its infection cycle to gain access to the long living memory B cell compartment. LMP1 and LMP2A are suggested to play an important role during this process, since they are able to provide B cells with survival and proliferation signals, and may help the EBV-infected B cells to evade negative selection during the germinal center reaction. LMP1 and LMP2A are also expressed in germinal center B cell derived EBV-associated malignancies, suggesting a contribution of these viral proteins to tumor development. However, the data concerning the role of the germinal center reaction in the latent EBV infection circle is controversial, remaining it elusive (i) if EBV-infected B cells have to pass the germinal center to establish persistence, and (ii) if LMP1 signaling has any influence on germinal center B cells. In the present work, the interplay of EBV and the germinal center reaction was examined, focusing on the roles of LMP1 and LMP2A in normal B cell biology and lymphomagenesis. LMP1 was shown to mimic a constitutive active CD40 receptor in vitro, but in vivo LMP1 only partially restored the CD40-deficiency in transgenic mice; it even blocked germinal center formation in the presence of CD40. This could be due to differences in the signaling mediated by LMP1 and CD40, or to the constitutive activity of LMP1. To compare CD40 and LMP1 signaling in vivo, we generated a transgenic mouse line which conditionally expresses a CD40-ligand regulated LMP1 protein (CD40/LMP1). We show that LMP1 signaling in B cells perfectly mimics CD40 function in vivo, leading to normal B cell development, B cell activation, and T cell dependent immune responses in CD40 deficient mice. Thus, we conclude that not the LMP1 signaling domain but its constitutive activity interferes with the germinal center reaction. This is in accordance with a previous study of our group, showing that ligand-independent constitutive active CD40 signaling (LMP1/CD40) blocks germinal center initiation like LMP1. However, the influence of a constitutive active CD40 signaling directly on germinal center B cells remained open. In the present study, LMP1/CD40 expression was specifically induced in germinal center B cells. We show that a constitutive active CD40 signaling also interferes with early germinal centers, but leads to lymphoproliferation, which most likely reflects malignant lymphoma. The incidence of 100% suggests a substantial risk of pre-activated B cells to become transformed upon deregulation of CD40 signaling or LMP1 expression. Since constitutive LMP1 and CD40 signals are not compatible with the germinal center B cell differentiation process, and LMP1 expression however has been detected in B cells resembling a germinal center phenotype of healthy EBV-carriers, we questioned whether these are real germinal center B cells. We studied the influence of EBV protein expression on the phenotype of human B cells in vitro, and indeed could show that EBNA2-independent LMP1 and LMP2A expression induces a germinal center cell like phenotype in B cells. Further, the inactivation of EBNA2, the key transactivator of EBV gene expression, does not lead to the original naïve phenotype of a B cell, but induces up-regulation of the memory B cell marker CD27. Beyond, we show that in CD40/LMP1-expressing B cells of the transgenic mice as well as in the human cell lines, LMP1 signaling induces class switch recombination independent from cytokines. This implies a unique feature of the LMP1 signaling domain to initiate differentiation processes beside its ability to activate B cells. Taking these data into account, we suggest that EBV infected B cells do not have to undergo a classical germinal center reaction to enter the memory B cell pool, but that with the help of EBV proteins they are able to induce processes imitating memory B cell differentiation independent from T cells, thus escaping immune surveillance. These EBV-infected quiescent memory-like B cells eventually enter the germinal center reaction upon antigen-dependent activation. There, re-induction of LMP1 might harbor a substantial risk of malignant transformation
Epstein-Barr virus nuclear antigen 1, Oct and Groucho/TLE in control of promoter regulation
No full textThe human herpes virus Epstein-Barr virus (EBV) is carried by approximately 95% of the adult population. It can form a lifelong latent infection in the B-cells by avoiding our immune system. A latent EBV infection is usually asymptomatic but a few EBV associated cancer forms has been described (e.g. Burkitt's lymphoma (BL)).EBV can avoid the immune system by restricting expression of its latent genes. Based on variation in viral gene expression several different latency forms have been described, e.g. latency 111 where all latency genes are expressed and latency 1 (e.g. BL) where only the nuclear protein EBNA l is expressed. EBNA l has three important functions, replication and maintenance of the viral genome and to regulate transcription. In latency 111 cells EBNA l is transcribed from the C promoter (Cp) together with six other proteins (EBNA l -6). The more restricted gene expression pattern in latency 1 cells is associated with a down regulation of the Cp and activity from the Q promoter (Qp) which leads to selective EBNA1 gene transcription. A switch between Cp and Qp usage might be instrumental in driving the host cell between latency forms. This thesis concerns the upstream control of Cp regulation with an emphasis on the interplay between cellular transcription factors and viral proteins.An EBNA1 responsive element called Family of Repeats (FR) is situated upstream of the Cp. EBNA1 can bind to each of the 20 repeats found in FR, thereby activating transcription. We have used various methods to show that the two cellular transcription factors Oct-1 and Oct-2 can bind to the FR sequence in vivo and in vitro and that the binding varies between the different repeats. We also show that binding has an impact on promoter activity in which Oct-2 alone and Oct-1 together with Bob.1 can substitute for the effect of EBNA1 on FR or further enhance the effect of EBNA1.We also describe the finding of a corepressor for Oct-proteins, namely the cellular protein Grg/TLE. The repression was shown to be highly dependent on the sequence to which Oct binds. This finding also applied to FR in EBV. All full-length Grg/TLE proteins as well as the truncated version Grg-5 can repress FR dependent Oct-2 activity. Binding of Grg/TLE to FR was also demonstrated both in vivo and in vitro. Repression by Grg/TLE could be cancelled by EBNA l, as well as the EBNA l induced activity could be repressed by Oct-2 + Grg/TLE.List of scientific papersI. Almqvist J, Zou J, Linderson Y, Borestrom C, Altiok E, Zetterberg H, Rymo L, Pettersson S, Ernberg I (2005). "Functional interaction of Oct transcription factors with the family of repeats in Epstein-Barr virus oriP." J Gen Virol 86(Pt 5): 1261-7 https://pubmed.ncbi.nlm.nih.gov/15831936II. Malin S, Linderson Y, Almqvist J, Ernberg I, Tallone T, Pettersson S (2005). "DNA-dependent conversion of Oct-1 and Oct-2 into transcriptional repressors by Groucho/TLE. " Nucleic Acids Res 33(14): 4618-25 https://pubmed.ncbi.nlm.nih.gov/16103132III. Almqvist J, Zou J, Pettersson S, Borestrom C, Rymo L, Ernberg I (2005). "Repression of Epstein-Barr virus enhancer family of repeats mediated transcription by Oct and Groucho/TLE transcriptional regulators, suggests an involvement in switching of latency programs." (Manuscript)IV. Zou J, Almqvist J, Ernberg I (2005). "Mapping of the Oct-binding sites in Epstein-Barr virus enhancer FR and demonstration of binding of Oct and Groucho/TLE in vivo." (Manuscript)</p
[Report to Chief J. E. Curry, by an unknown author #1]
No full textReport to Chief J. E. Curry, by an unknown author. The report contains a list of officers who gave depositions to the United States Attorney
[Report to Chief J. E. Curry, by an unknown author #2]
No full textReport to Chief J. E. Curry, by an unknown author. The report contains a list of officers who gave depositions to the United States Attorney
Epstein-Barr virus latency in transplant patients and healthy carriers
No full textIn this thesis, I studied the latency situation of Epstein-Barr virus (EBV) in bone marrow transplanted (BMT) patients and healthy virus carriers.Paper 1: Epstein-Barr virus genomes are found predominantly in lgA-positive B cells in the blood of healthy carriers. B lymphocytes have been identified as the main reservoir of latent Epstein-Barr virus (EBV) in healthy virus carriers. We have established a semi-quantitative PCR method (SQ-PCR) to estimate the EBV genome load in the blood B-cell subpopulation in healthy individuals. EBV DNA was detected in subfractionated IgM-, IgG- and IgA-positive B cells. Between 80% and 90% of the viral DNA was found in the lgA-positive compared with the IgA-negative fraction.Paper 2: Epstein-Barr virus (EBV) load in bone marrow transplant (BMT) recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells. We used same SQ-PCR as reported in paper 1 to monitor the blood levels of EBVDNA in 9 patients receiving allogeneic BMT. Four of 5 recipients of HLA-mismatched T-cell-depleted grafts showed a 4- to 5-log increase of EBV-DNA within 1 to 3 months after BMT. Administration of 2 to 4 infusions of 107 EBV-specific cytotoxic T-lymphocytes (CTLS)/M2 starting from the time of maximal virus load resulted in a 2- to 3-log decrease of virus titers in 3 patients. One patient, who received a T-cell culture lacking a major EBV-specific component, progressed to fatal EBV-positive lymphoma. Administration of EBVCTLs before the onset of the EBV-DNA peak resulted in stabilization of the virus titers within 2 to 3 logs above the normal levels in the fifth patient.A moderate increase of virus titers was also detected in 3 of 4 patients receiving unmanipulated HLA-matched grafts, whereas one patient with Wiskott-Aldrich syndrome (WAS) reached a 5-log increase of EBV-DNA load within 70 days after BMT. Our results suggest that a rapid increase of circulating EBV-DNA occurs in the absence of EBV-specific T-cell precursors or in the presence of congenital immune defects that prevent the reestablishment of virus-specific immunity. Prophylactic administration of EBV-CTLs early after BMT appears to provide the most effective protection against the development of EBV-associated lymphoproliferative disease.Paper 3: Circulating Epstein-Barr virus infected "resting" B lymphocytes in bone marrow transplant recipients at risk to develop post-transplant lymphoproliferative disease. EBV establishes a life long infection of humans where the proliferative potential of latently infected B blasts is kept in cheek by strong T-cell mediated rejection responses. A key feature of this virus host relationship is the capacity of the virus to establish a restricted latent infection in resting B cells that are insensitive to rejection and provide a reservoir for reactivation and spread to susceptible hosts. In immunosuppressed individuals the EBV-infected blasts may give rise to lymphoproliferative disorders that are preceded by a dramatic increase of virus load in blood. We have used SQ-PCR assays and reverse transcriptase assisted (RT)-PCRs to investigate the EBV-DNA load and the pattern of viral gene expression in peripheral blood of immunosuppressed patients receiving T cell depleted or unmanipulated bone marrow grafts from healthy EBV carriers.Patients in both groups showed a significant increase of EBV-DNA load compared to healthy controls. Virus titers exceeding the normal levels by more than 4 logs were detected in recipients of T-cell depleted marrow and in one patient with Wiskott-Aldrich syndrome. Measurement of EBV-DNA in serum and limiting dilution analysis of EBV-DNA in PBMC demonstrated that the increased virus load is due to expansion of a latently infected cell compartment that contains less than 10 EBV genomes copies per cell and expresses EBERs, LMP-2A and occasionally LMP 1 and EBNA 1 but not other latency associated viral proteins that serve as targets for virus-specific immune responses. This is compatible with latency forms I-II in non proliferating B-cells, but not latency Ill.Administration of EBV-specific CTLs correlated with a slow decrease of EBV-DNA load followed by stabilization at levels significantly higher then in healthy controls. The results suggest that suppression of EBV-specific T cell responses allows the proliferation infected B blasts in lymphoid tissues and that these cells retain the capacity to differentiate into resting B cells that enter the circulation. Reconstitution of T cell immunity results in the establishment of a new virus host-balance characterised by a significant expansion of the latent viral reservoir.The following main conclusions could be drawn from our results: · EBV can infect IgM-, IgG- and IgA-positive B cells. Between 80% and 90% of the viral DNA was found in the IgA-positive subfraction; · HLA-mismatched T-cell-depleted grafts showed a 4- to 5-log increase of EBV-DNA within 1 to 3 months after BMT; · Administration of EBV-CTLs early after BMT appears to provide the most effective protection against the development of EBV-associated lymphoproliferative disease; · In BMT patients, EBV is in latency forms I-II in non proliferating B-cells, neither latency 111 nor infected B cells in lytic cycle .List of scientific papersI. Ehlin-Henriksson B, Zou JZ, Klein G, Ernberg I (1999). Epstein-Barr virus genomes are found predominantly in IgA-positive B cells in the blood of healthy carriers. Int J Cancer. 83(1): 50-4. https://pubmed.ncbi.nlm.nih.gov/10449607II. Gustafsson A, Levitsky V, Zou JZ, Frisan T, Dalianis T, Ljungman P, Ringden O, Winiarski J, Ernberg I, Masucci MG (2000). Epstein-Barr virus (EBV) load in bone marrow transplant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells. Blood. 95(3): 807-14. https://pubmed.ncbi.nlm.nih.gov/10648390III. Zou JZ, Levitsky V, Gustafss A, Frisan T, Dalianis T, Ljungman P, Ringden O, Winiaski J, Masucci MG, Ernberg I (2005). Circulating Epstein-Barr virus infected "resting" B lymphocytes in bone marrow transplant recipients at risk to develop post-transplant lymphoproliferative disease. [Manuscript]</p
Immunodominance of lytic cycle antigens in Epstein-Barr virus-specific CD4+ T cell preparations for therapy.
No full textEpstein-Barr virus (EBV) is associated with a number of human malignancies. EBV-positive post-transplant lymphoproliferative disease in solid organ and hematopoietic stem cell transplant recipients has been successfully treated by the adoptive transfer of polyclonal EBV-specific T cell lines containing CD4+ and CD8+ T cell components. Although patients receiving T cell preparations with a higher CD4+ T cell proportion show better clinical responses, the specificity of the infused CD4+ component has remained completely unknown.
We generated LCL-stimulated T cell lines from 21 donors according to clinical protocols, and analyzed the antigen specificity of the CD4+ component in EBV-specific T cell preparations using a genetically engineered EBV mutant that is unable to enter the lytic cycle, and recombinantly expressed and purified EBV proteins. Surprisingly, CD4+ T cell lines from acutely and persistently EBV-infected donors consistently responded against EBV lytic cycle antigens and autoantigens, but barely against latent cycle antigens of EBV hitherto considered principal immunotherapeutic targets. Lytic cycle antigens were predominantly derived from structural proteins of the virus presented on MHC II via receptor-mediated uptake of released viral particles, but also included abundant infected cell proteins whose presentation involved intercellular protein transfer. Importantly, presentation of virion antigens was severely impaired by acyclovir treatment of stimulator cells, as currently performed in most clinical protocols.
These results indicate that structural antigens of EBV are the immunodominant targets of CD4+ T cells in LCL-stimulated T cell preparations. These findings add to our understanding of the immune response against this human tumor-virus and have important implications for the improvement of immunotherapeutic strategies against EBV
- …
