A. Rickinson | The University of Birmingham (original) (raw)

Papers by A. Rickinson

Research paper thumbnail of Novel transcription from the Epstein-Barr virus terminal EcoRI fragment, DIJhet, in a nasopharyngeal carcinoma

Journal of virology, 1990

Transcription of Epstein-Barr virus (EBV) genes in epithelial tissue, one of the two principal ce... more Transcription of Epstein-Barr virus (EBV) genes in epithelial tissue, one of the two principal cell types infected by EBV, is not well characterized. EBV transcription in a nasopharyngeal carcinoma established in nude mice, C15, has been analyzed by using strand-specific RNA probes and sequence analysis of a C15 cDNA library. In C15, two equally abundant mRNAs of 3.7 and 2.8 kilobases (kb) are encoded by the sequences that encode latent membrane protein (LMP). Hybridization with probes specific for the 3' end of the LMP mRNA to Northern (RNA) blots and sequence analysis of cDNAs representing the messages indicated that the 3.7- and 2.8-kb mRNAs are 3' coterminal. Sequence analysis of additional cDNAs revealed an mRNA that is spliced identically to the LMP mRNA but is initiated 5' to the promoter for LMP. A probe representing the sequences contained within the cDNA which are 5' to the LMP promoter identified the 3.7-kb mRNA in C15 and a low-abundance 3.7-kb mRNA in B9...

Research paper thumbnail of Human CD8+ T cell responses to EBV EBNA1: HLA class I presentation of the (Gly-Ala)-containing protein requires exogenous processing

Immunity, 1997

Epstein-Barr virus (EBV)-induced cytotoxic T lymphocyte (CTL) responses have been detected agains... more Epstein-Barr virus (EBV)-induced cytotoxic T lymphocyte (CTL) responses have been detected against many EBV antigens but not the nuclear antigen EBNA1; this has been attributed to the presence of a glycine-alanine repeat (GAr) domain in the protein. Here we describe the isolation of human CD8+ CTL clones recognizing EBNA1-specific peptides in the context of HLA-B35.01 and HLA-A2.03. Using these clones, we show that full-length EBNA1 is not presented when expressed endogenously in target cells, whereas the GAr-deleted form is presented efficiently. However, when supplied as an exogenous antigen, the full-length protein can be presented on HLA class I molecules by a TAP-independent pathway; this may explain how EBNA1-specific CTLs are primed in vivo.

Research paper thumbnail of Epstein-Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death

Proceedings of the National Academy of Sciences of the United States of America, Jan 15, 1993

Epstein-Barr virus, a human herpesvirus that persists within the B-lymphoid system, can enhance t... more Epstein-Barr virus, a human herpesvirus that persists within the B-lymphoid system, can enhance the survival potential of latently infected B cells in vitro through up-regulation of the cellular survival protein Bcl-2. The possibility that an analogous effect is operative in lytically infected cells was suggested by the observation of distant sequence homology between an Epstein-Barr virus-coded early lytic cycle protein, BHRF1, and Bcl-2. Here we show by gene transfer that BHRF1 resembles Bcl-2 both in its subcellular localization and in its capacity to enhance B-cell survival. Thus confocal microscopic analysis of cells acutely cotransfected with BHRF1 and Bcl-2 expression vectors revealed substantial colocalization of the two proteins in the cytoplasm. In subsequent experiments, stable BHRF1 gene transfectants of Burkitt lymphoma cells paralleled Bcl-2 transfectants in their enhanced survival under conditions that induce cell death by apoptosis. Despite their limited sequence con...

Research paper thumbnail of QUANTITATION OF EPSTEIN-BARR VIRUS DNA IN THE BLOOD OF ADULT LIVER TRANSPLANT RECIPIENTS1

Transplantation, 2000

Background. Posttransplant lymphoproliferation is most often observed in pediatric transplant rec... more Background. Posttransplant lymphoproliferation is most often observed in pediatric transplant recipients who experience primary Epstein-Barr virus (EBV) infection at the time of or after transplantation. Lymphoproliferation is believed to be caused by impaired control of EBV-infected cells, which may be of recipient or donor origin. Most studies of EBV infection and lymphoproliferation have focused on the pediatric age group.

Research paper thumbnail of Epstein-Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death

Proceedings of the National Academy of Sciences, 1993

Epstein-Barr virus, a human herpesvirus that persists within the B-lymphoid system, can enhance t... more Epstein-Barr virus, a human herpesvirus that persists within the B-lymphoid system, can enhance the survival potential of latently infected B cells in vitro through up-regulation of the cellular survival protein Bcl-2. The possibility that an analogous effect is operative in lytically infected cells was suggested by the observation of distant sequence homology between an Epstein-Barr virus-coded early lytic cycle protein, BHRF1, and Bcl-2. Here we show by gene transfer that BHRF1 resembles Bcl-2 both in its subcellular localization and in its capacity to enhance B-cell survival. Thus confocal microscopic analysis of cells acutely cotransfected with BHRF1 and Bcl-2 expression vectors revealed substantial colocalization of the two proteins in the cytoplasm. In subsequent experiments, stable BHRF1 gene transfectants of Burkitt lymphoma cells paralleled Bcl-2 transfectants in their enhanced survival under conditions that induce cell death by apoptosis. Despite their limited sequence conservation, therefore, the two proteins appear to be functionally homologous. We suggest that BHRF1 provides an alternative, Bcl-2-independent, means of enhancing B-cell survival that may operate during the virus lytic cycle.

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

Journal of Virology, 2001

Human CD4 ؉ T-helper 1 cell responses to Epstein-Barr virus (EBV) infection are likely to be impo... more 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 Ͼ Ͼ Ͼ Ͼ LMP1, LMP2) which is different from that identified for the same proteins with respect to CD8 ؉ -T-cell responses (EBNA3C > EBNA1 > LMP2 Ͼ Ͼ Ͼ Ͼ 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 ؉ -Tcell frequencies.

Research paper thumbnail of Novel transcription from the Epstein-Barr virus terminal EcoRI fragment, DIJhet, in a nasopharyngeal carcinoma

Journal of virology, 1990

Transcription of Epstein-Barr virus (EBV) genes in epithelial tissue, one of the two principal ce... more Transcription of Epstein-Barr virus (EBV) genes in epithelial tissue, one of the two principal cell types infected by EBV, is not well characterized. EBV transcription in a nasopharyngeal carcinoma established in nude mice, C15, has been analyzed by using strand-specific RNA probes and sequence analysis of a C15 cDNA library. In C15, two equally abundant mRNAs of 3.7 and 2.8 kilobases (kb) are encoded by the sequences that encode latent membrane protein (LMP). Hybridization with probes specific for the 3' end of the LMP mRNA to Northern (RNA) blots and sequence analysis of cDNAs representing the messages indicated that the 3.7- and 2.8-kb mRNAs are 3' coterminal. Sequence analysis of additional cDNAs revealed an mRNA that is spliced identically to the LMP mRNA but is initiated 5' to the promoter for LMP. A probe representing the sequences contained within the cDNA which are 5' to the LMP promoter identified the 3.7-kb mRNA in C15 and a low-abundance 3.7-kb mRNA in B9...

Research paper thumbnail of Human CD8+ T cell responses to EBV EBNA1: HLA class I presentation of the (Gly-Ala)-containing protein requires exogenous processing

Immunity, 1997

Epstein-Barr virus (EBV)-induced cytotoxic T lymphocyte (CTL) responses have been detected agains... more Epstein-Barr virus (EBV)-induced cytotoxic T lymphocyte (CTL) responses have been detected against many EBV antigens but not the nuclear antigen EBNA1; this has been attributed to the presence of a glycine-alanine repeat (GAr) domain in the protein. Here we describe the isolation of human CD8+ CTL clones recognizing EBNA1-specific peptides in the context of HLA-B35.01 and HLA-A2.03. Using these clones, we show that full-length EBNA1 is not presented when expressed endogenously in target cells, whereas the GAr-deleted form is presented efficiently. However, when supplied as an exogenous antigen, the full-length protein can be presented on HLA class I molecules by a TAP-independent pathway; this may explain how EBNA1-specific CTLs are primed in vivo.

Research paper thumbnail of Epstein-Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death

Proceedings of the National Academy of Sciences of the United States of America, Jan 15, 1993

Epstein-Barr virus, a human herpesvirus that persists within the B-lymphoid system, can enhance t... more Epstein-Barr virus, a human herpesvirus that persists within the B-lymphoid system, can enhance the survival potential of latently infected B cells in vitro through up-regulation of the cellular survival protein Bcl-2. The possibility that an analogous effect is operative in lytically infected cells was suggested by the observation of distant sequence homology between an Epstein-Barr virus-coded early lytic cycle protein, BHRF1, and Bcl-2. Here we show by gene transfer that BHRF1 resembles Bcl-2 both in its subcellular localization and in its capacity to enhance B-cell survival. Thus confocal microscopic analysis of cells acutely cotransfected with BHRF1 and Bcl-2 expression vectors revealed substantial colocalization of the two proteins in the cytoplasm. In subsequent experiments, stable BHRF1 gene transfectants of Burkitt lymphoma cells paralleled Bcl-2 transfectants in their enhanced survival under conditions that induce cell death by apoptosis. Despite their limited sequence con...

Research paper thumbnail of QUANTITATION OF EPSTEIN-BARR VIRUS DNA IN THE BLOOD OF ADULT LIVER TRANSPLANT RECIPIENTS1

Transplantation, 2000

Background. Posttransplant lymphoproliferation is most often observed in pediatric transplant rec... more Background. Posttransplant lymphoproliferation is most often observed in pediatric transplant recipients who experience primary Epstein-Barr virus (EBV) infection at the time of or after transplantation. Lymphoproliferation is believed to be caused by impaired control of EBV-infected cells, which may be of recipient or donor origin. Most studies of EBV infection and lymphoproliferation have focused on the pediatric age group.

Research paper thumbnail of Epstein-Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death

Proceedings of the National Academy of Sciences, 1993

Epstein-Barr virus, a human herpesvirus that persists within the B-lymphoid system, can enhance t... more Epstein-Barr virus, a human herpesvirus that persists within the B-lymphoid system, can enhance the survival potential of latently infected B cells in vitro through up-regulation of the cellular survival protein Bcl-2. The possibility that an analogous effect is operative in lytically infected cells was suggested by the observation of distant sequence homology between an Epstein-Barr virus-coded early lytic cycle protein, BHRF1, and Bcl-2. Here we show by gene transfer that BHRF1 resembles Bcl-2 both in its subcellular localization and in its capacity to enhance B-cell survival. Thus confocal microscopic analysis of cells acutely cotransfected with BHRF1 and Bcl-2 expression vectors revealed substantial colocalization of the two proteins in the cytoplasm. In subsequent experiments, stable BHRF1 gene transfectants of Burkitt lymphoma cells paralleled Bcl-2 transfectants in their enhanced survival under conditions that induce cell death by apoptosis. Despite their limited sequence conservation, therefore, the two proteins appear to be functionally homologous. We suggest that BHRF1 provides an alternative, Bcl-2-independent, means of enhancing B-cell survival that may operate during the virus lytic cycle.

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

Journal of Virology, 2001

Human CD4 ؉ T-helper 1 cell responses to Epstein-Barr virus (EBV) infection are likely to be impo... more 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 Ͼ Ͼ Ͼ Ͼ LMP1, LMP2) which is different from that identified for the same proteins with respect to CD8 ؉ -T-cell responses (EBNA3C > EBNA1 > LMP2 Ͼ Ͼ Ͼ Ͼ 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 ؉ -Tcell frequencies.