Immune regulation of Epstein-Barr virus (EBV): EBV nuclear antigen as a target for EBV-specific T cell lysis

Moss, Denis J.; Misko, Ihor S.; Sculley, T. B.; Apolloni, Ann; Khanna, Rajiv; Burrows, Scott R.

doi:10.1007/bf00201465

Cited by 11 publications

(6 citation statements)

References 45 publications

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“…Construction of a thymidine kinase (TK)-negative recombinant virus was carried out by using protocols for marker rescue recombination between pSTPT1 and VV-WR-L929 described previously (22). Plaque (17)(18)(19)(20). The target cells used in Fig.…”

Section: Methodsmentioning

confidence: 99%

Minimal epitopes expressed in a recombinant polyepitope protein are processed and presented to CD8+ cytotoxic T cells: implications for vaccine design.

Thomson

Khanna

Gardner

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

130

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The epitopes recognized by CD8+ cytotoxic T lymphocytes (CTL) are generated from cytosolic proteins by proteolytic processing. CD8+ a3 cytotoxic T lymphocytes (CTL) recognize short peptides (epitopes) associated with specific alleles of the class I major histocompatibility complex (1). The peptide epitopes are mainly generated from cytosolic proteins by proteolysis, a process believed to involve the multicatalytic proteosome complex (2-8). The influence of sequences flanking CTL epitopes on the proteolytic processing and presentation of these epitopes remains controversial (9-14). Moving CTL epitopes into new positions within a protein in some cases prevents (9) and in other cases has no effect on (10, 11) presentation of the epitope. A profound effect on presentation was observed when an epitope was expressed with different truncations of the natural flanking sequences (12). However, only one of a series of substitutions made to the amino acid residues flanking a CTL epitope was shown to effect presentation (13,14). The subdominance of a CTL epitope has been attributed to the inability of proteosomes to generate the peptide from the parent protein (15), although recently the subdominance of this epitope has been attributed to low affinity of the peptide for its restriction element (16). Although some of these data may illustrate that certain flanking sequences prevent proteolytic generation of an epitope, it is not clear whether the presence of any specific natural flanking sequences is needed to direct the activity of proteolytic processing enzymes.To determine whether any natural sequences outside CTL epitopes are a requirement for class I processing, a recombinant vaccinia virus (VV) was constructed that coded for a single artificial polyepitope protein containing nine class I-restricted CD8+ CTL epitopes in sequence (see Fig.

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Section: Methodsmentioning

confidence: 99%

Minimal epitopes expressed in a recombinant polyepitope protein are processed and presented to CD8+ cytotoxic T cells: implications for vaccine design.

Thomson

Khanna

Gardner

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

130

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“…Interestingly, this sequence does not contain either a glutamate at position 2 or a tyrosine at position 9 or 10, both recently identified as common features of HLA-B44.03-binding peptides (8). In contrast, the two previously published B44-restricted epitopes in EBNA3C do accord with the above-mentioned motif (6,32). Our preliminary evidence suggests that donor CMc possesses the B44.02 allele rather than the B44.03 allele; this could explain the difference in B44 epitope choice.…”

Section: Vol 70 1996mentioning

confidence: 70%

“…To characterize further the specificity of this response, we sought to identify the peptide epitope(s) against which it was directed. Two B44-restricted CTL epitopes (EBNA3C residues 281 through 290 and 335 through 343) have been reported in the literature (6,32), but neither of these sequences was recognized by any CMc clone in peptide sensitization assays (data not shown). Therefore, we used one of the clones to screen a set of overlapping peptides (15-and 16-mers overlapping by 10 and 11 residues, respectively) which cover the entire EBNA3C sequence.…”

Section: Expression Of Ebna3c From the Rad-e3c Vectormentioning

confidence: 93%

“…4). In the case of donor CMc, preliminary studies indicated that the RAd-E3C-induced response was HLA-B44 restricted, but we were concerned to find that reactivated CTL clones did not recognize either of the previously published B44-restricted EBNA3C peptides (6,32). To demonstrate the EBNA3C specificity of these effectors, we screened a complete panel of overlapping peptides from the EBNA3C sequence and thereby mapped a new B44-restricted epitope, EGGVGWRHW (Fig.…”

Section: Vol 70 1996mentioning

confidence: 99%

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A recombinant adenovirus expressing an Epstein-Barr virus (EBV) target antigen can selectively reactivate rare components of EBV cytotoxic T-lymphocyte memory in vitro

Morgan

Wilkinson

Floettmann

et al. 1996

J Virol

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While the bulk of a virus-induced cytotoxic T-lymphocyte (CTL) response may focus on a few immunodominant viral antigens, in certain tumor virus systems the detectability of clones recognizing other, subdominantantigens can assume particular importance. By using the human CTL response to Epstein-Barr virus (EBV) as a model system, here we show that even rare components of virus-specific memory can be selectively reactivated in vitro when the relevant target antigen is expressed in autologous stimulator cells from a recombinant adenovirus (RAd) vector. We generated a replication-deficient adenovirus, RAd-E3C, which in skin fibroblast cultures expressed the EBV nuclear antigen EBNA3C at a 10-to 100-fold-higher level than that naturally present in EBV-transformed lymphoblastoid cell lines (LCLs). Initial experiments with a donor whose polyclonal CTL response to LCL stimulation contained a strong EBNA3C-specific component showed that these CTLs could be efficiently reactivated by in vitro stimulation either with RAd-E3C-infected fibroblasts or with RAd-E3C-infected peripheral blood mononuclear cells. Then we studied donors whose responses to LCL stimulation contained little if any detectable EBNA3C reactivity but were dominated by clones recognizing other EBV target antigens; in vitro stimulation with RAd-E3C-infected peripheral blood mononuclear cells selectively reactivated EBNA3C-specific CTL clones from these individuals, with the epitope specificities of responses subsequently identified at the peptide level. This RAd-based approach could be applied more generally to screen for human CTL responses against any candidate target antigen expressed by tumor cells.

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“…Conceivably, it would be in the best interest of a persistent virus to generate less pathogenic variants for maintenance of the chronic carrier state. Moreover, in a highly primed immunologic environment, loss of EBNA2 (one of the genes thought to mediate cytotoxic T cell responses to EBV infection [38][39][40]) may assist in EBV's escape from immunoregulation. It is tempting to speculate that such an EBNA2-deleted EBV could replicate in a relatively unperturbed host, perhaps in the mucosal epithelium, until such time as recombination with a latent, transformation-competent virus facilitated reentry of a fully pathogenic chimera into the lymphoid pool.…”

Section: Transformation-incompetent Ebv At Mucosal Sitesmentioning

confidence: 99%

Epstein-Barr virus infection at mucosal surfaces: detection of genomic variants with altered pathogenic potential

Sixbey

Shirley

1991

Springer Semin Immunopathol

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Immune regulation of Epstein-Barr virus (EBV): EBV nuclear antigen as a target for EBV-specific T cell lysis

Cited by 11 publications

References 45 publications

Minimal epitopes expressed in a recombinant polyepitope protein are processed and presented to CD8+ cytotoxic T cells: implications for vaccine design.

Minimal epitopes expressed in a recombinant polyepitope protein are processed and presented to CD8+ cytotoxic T cells: implications for vaccine design.

A recombinant adenovirus expressing an Epstein-Barr virus (EBV) target antigen can selectively reactivate rare components of EBV cytotoxic T-lymphocyte memory in vitro

Epstein-Barr virus infection at mucosal surfaces: detection of genomic variants with altered pathogenic potential

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