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  • 1
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 3110-3110
    Abstract: Objective: EBV-specific CD8+ T cells have been extensively studied in various settings, and appear to play a major role in the control of EBV-related malignancies. In contrast, it is still unclear whether EBV-specific CD4+ T cells play a role in vivo. To study this question, an assay was developed to measure the CD4+ T-cell response towards two EBV antigens, in both healthy (n=14) and HIV-infected subjects (n=23). In addition, both HAART-treated (n=12) and untreated HIV+ individuals (n=14) - including progressors to EBV-related lymphoma - were studied longitudinally. Methods: EBV-specific CD4+ T cells were stimulated with peptide pools from latent protein EBNA1 and lytic protein BZLF1, and detected by measurement of IFNg-production. Results: After direct ex vivo stimulation, EBNA1 or BZLF1-specific IFNg- (and/or IL2) producing CD4+ T cell numbers were low, and measurable in less than half of the subjects studied (either HIV- and HIV+). Therefore, PBMC were cultured for 12 days in the presence of peptides and IL2 (from day 3), and then restimulated with peptides, allowing specific and reproducible expansion of EBV-specific CD4+ T cells, independent of HLA type and ex vivo antigen processing. Interestingly, numbers of EBV-specific CD4+ T cells inversely correlated with EBV viral load, implying an important role for EBV-specific CD4+ T cells in the control of EBV in vivo. Untreated HIV-infected individuals had a lower CD4+ T cell response to EBNA1 and BZLF1 as compared to healthy EBV carriers and HAART-treated HIV+ subjects. In longitudinal samples, EBNA1-specific, but not BZLF1-specific T-cell numbers increased after HAART, while EBV load was not affected by treatment. In all the progressors to EBV-related lymphoma, EBV-specific CD4+ T cells were lost at least 24 months before lymphoma diagnosis. Conclusions: Both cross-sectional and longitudinal data suggest an important role for EBV-specific CD4+ T cells in the control of EBV-related malignancies. Furthermore, it seems that HAART treatment leads to recovery of EBNA1-specific, but not BZLF1-specific CD4+ T-cell responses, implying changes in the latency pattern of EBV, despite an unaltered cell-associated EBV DNA load. Thus, early HAART treatment might prevent loss of specific CD4+ T-cell help and progression to NHL.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
    In: European Journal of Immunology, Wiley, Vol. 35, No. 3 ( 2005-03), p. 796-805
    Abstract: A lower function of EBV‐specific CD8 + T cells in HIV‐infected subjects could be related to a lack of specific CD4 + T cell help. Therefore, we studied EBV‐specific CD4 + T cells in both healthy donors and untreated or highly active antiretroviral therapy (HAART)‐treated HIV‐seropositive homosexual men. To this end, PBMC were stimulated with overlapping peptide pools from a latent and a lytic EBV protein, EBV nuclear antigen (EBNA)1 and EBV lytic‐switch protein ZEBRA (BZLF1), respectively. EBV‐specific CD4 + T cell frequencies measured directly ex vivo were low. To measure EBV‐specific memory CD4 + T cells, capable of both expansion and IFN‐γ production upon antigenic challenge, we developed a specific and reproducible assay, combining ex vivo expansion of specific T cells with flow cytometric analysis of IFN‐γ production. Untreated HIV‐infected individuals had a lower CD4 + T cell response to both EBNA1 and BZLF1 as compared to healthy EBV carriers and HAART‐treated HIV‐positive subjects. This suggests loss of EBV‐specific CD4 + T cells due to HIV infection, while HAART might restore this response. In addition, we found an increase in the EBNA1‐specific CD8 + T cell response in HAART‐treated subjects. Interestingly, numbers of EBV‐specific CD4 + and CD8 + T cells were inversely correlated with EBV viral load, suggesting an important role also for EBV‐specific CD4 + T cells in the control of EBV infection.
    Type of Medium: Online Resource
    ISSN: 0014-2980 , 1521-4141
    URL: Issue
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    Language: English
    Publisher: Wiley
    Publication Date: 2005
    detail.hit.zdb_id: 1491907-2
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  • 3
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 172, No. 11 ( 2004-06-01), p. 6931-6937
    Abstract: In contrast to the situation in the post-transplant setting, in HIV-infected individuals an elevated EBV load is not predictive of EBV-related malignancies. To study whether a high EBV load is already a normal situation early in HIV infection and is not related to a decrease in immune function over time, we investigated EBV load and EBV-specific CD8+ T cells ∼1 year before and 1 year after HIV seroconversion. EBV load significantly increased after HIV seroconversion from 205 to 1002 copies/106 PBMC (p & lt; 0.001), whereas no further increase in EBV load was observed between 1 and 5 years after HIV seroconversion (median, 1827–2478 copies/106 PBMC; p = 0.530). Interestingly, the absolute number of EBV lytic epitope, RAKFKQLL-specific CD8+ T cells increased over HIV seroconversion (4.78 to 9.54/μl; p = 0.011). Furthermore, the fraction of CD27-negative effector, RAK-specific CD8+ T cells tended to increase (from 12.2 to 17.31% CD27−; p = 0.051), in accordance with Ag-driven differentiation. In conclusion, both virological and immunological data support the idea that a new EBV viral setpoint is reached early in HIV infection, probably by EBV reactivation, as suggested by the preferential increase in EBV lytic epitope-specific CD8+ T cells. These data may thus help to explain the lack of predictive value of EBV load for the occurrence of AIDS-related lymphoma.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
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    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2004
    detail.hit.zdb_id: 1475085-5
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  • 4
    In: International Journal of Cancer, Wiley, Vol. 136, No. 6 ( 2015-03-15), p. 1371-1380
    Abstract: What's New? Activation‐induced cytidine deaminase (AID) expression has been linked to translocations in the c‐myc transcription factor that can cause Burkitt's lymphoma, a tumor closely associated with Epstein Barr Virus (EBV) and malaria infections. Here the authors demonstrate a first link between AID expression and exposure to malaria in the peripheral blood of children. They further show that AID expression is linked to detectable EBV in children living in a region of high malaria transmission. These findings shed new light on how malaria and EBV co‐infections can increase the risk of developing Burkitt's lymphoma.
    Type of Medium: Online Resource
    ISSN: 0020-7136 , 1097-0215
    URL: Issue
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    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 218257-9
    detail.hit.zdb_id: 1474822-8
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