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Pathogenesis and Immunity

Differential Immunogenicity of Epstein-Barr Virus Latent-Cycle Proteins for Human CD4+ T-Helper 1 Responses

Ann Leen, Pauline Meij, Irina Redchenko, Jaap Middeldorp, Elisabeth Bloemena, Alan Rickinson, Neil Blake
Ann Leen
CRC Institute for Cancer Studies and MRC Centre for Immune Regulation, Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom,and
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Pauline Meij
Department of Pathology, Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands
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Irina Redchenko
CRC Institute for Cancer Studies and MRC Centre for Immune Regulation, Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom,and
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Jaap Middeldorp
Department of Pathology, Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands
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Elisabeth Bloemena
Department of Pathology, Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands
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Alan Rickinson
CRC Institute for Cancer Studies and MRC Centre for Immune Regulation, Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom,and
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Neil Blake
CRC Institute for Cancer Studies and MRC Centre for Immune Regulation, Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom,and
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DOI: 10.1128/JVI.75.18.8649-8659.2001
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ABSTRACT

Human CD4+ T-helper 1 cell responses to Epstein-Barr virus (EBV) infection are likely to be important in the maintenance of virus-specific CD8+ memory and/or as antiviral effectors in their own right. The present work has used overlapping peptides as stimulators of gamma interferon release (i) to identify CD4+ epitopes within four EBV latent-cycle proteins, i.e., the nuclear antigens EBNA1 and EBNA3C and the latent membrane proteins LMP1 and LMP2, and (ii) to determine the frequency and magnitude of memory responses to these proteins in healthy virus carriers. Responses to EBNA1 and EBNA3C epitopes were detected in the majority of donors, and in the case of EBNA1, their antigen specificity was confirmed by in vitro reactivation and cloning of CD4+ T cells using protein-loaded dendritic cell stimulators. By contrast, responses to LMP1 and LMP2 epitopes were seen much less frequently. EBV latent-cycle proteins therefore display a marked hierarchy of immunodominance for CD4+ T-helper 1 cells (EBNA1, EBNA3C ≫ LMP1, LMP2) which is different from that identified for the same proteins with respect to CD8+-T-cell responses (EBNA3C > EBNA1 > LMP2 ≫ LMP1). Furthermore, the range of CD4+ memory T-cell frequencies in peripheral blood of healthy virus carriers was noticeably lower and narrower than the corresponding range of latent antigen-specific CD8+-T-cell frequencies.

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Differential Immunogenicity of Epstein-Barr Virus Latent-Cycle Proteins for Human CD4+ T-Helper 1 Responses
Ann Leen, Pauline Meij, Irina Redchenko, Jaap Middeldorp, Elisabeth Bloemena, Alan Rickinson, Neil Blake
Journal of Virology Sep 2001, 75 (18) 8649-8659; DOI: 10.1128/JVI.75.18.8649-8659.2001

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Differential Immunogenicity of Epstein-Barr Virus Latent-Cycle Proteins for Human CD4+ T-Helper 1 Responses
Ann Leen, Pauline Meij, Irina Redchenko, Jaap Middeldorp, Elisabeth Bloemena, Alan Rickinson, Neil Blake
Journal of Virology Sep 2001, 75 (18) 8649-8659; DOI: 10.1128/JVI.75.18.8649-8659.2001
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KEYWORDS

Epitopes, T-Lymphocyte
Epstein-Barr Virus Nuclear Antigens
Herpesvirus 4, Human
Th1 cells
Viral Matrix Proteins
Virus Latency

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