Epstein-Barr virus (EBV) is associated with several important human malignancies. It is now well established that cytotoxic T lymphocytes (CTLs) play a critical role in controlling the level of EBV-infected B cells which express a family of latent viral antigens, including EBNAs 1,2,3,4,5 and 6. These latent antigens include CTL epitopes that are presented on the surface of virus-infected cells in conjunction with class I antigens. This proposal is designed to assess, for the first time, the capacity of an EBV CTL peptide epitope (EBNA3 derived/HLA B8 restricted) to activate a primary response in vivo in a cohort of human volunteers. These volunteers will be selected from healthy laboratory and army personnel. If successful, this proposal would establish the potential use of synthetic peptides in the development of a subunit vaccine to EBV and to other human oncogenic viruses where it is unlikely that attenuated strains will ever be accepted as a vaccination procedure. The other major aspect of the proposal relates to the mechanisms whereby EBV-associated tumors escape immune surveillance. Particular attention will be focused on Burkitt's lymphoma (BL) which express only EBNA1. Thus far, no CTL epitopes have been localized on EBNA1. The present proposal seeks to demonstrate unequivocally whether EBNA1 includes CTL epitopes. If CTL epitopes are identified in EBNA1, it will be important to determine whether BL cells process and present these epitopes. These studies are designed to delineate how BL cells escape immunological recognition. The methodology to be used in the proposal includes the following: The activation of an EBV-specific response in vivo will be monitored using a standard EBV regression assay, clonal and polyclonal CTL assays and limiting dilution analysis. The sensitivity of BL cells to CTL lysis will be determined following the treatment of tumor cells with appropriate synthetic peptides, vaccinia constructs and transfected episomal viral mini-gene expression vectors. The presence of CTL epitopes within EBNA1 will be assessed by activating an EBNA1-specific response in human and mouse cells using recombinant EBNA1.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA057952-03
Application #
2098663
Study Section
Special Emphasis Panel (SRC (66))
Project Start
1992-08-17
Project End
1996-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Queensland Institute of Medical Research
Department
Type
DUNS #
758815328
City
Herston
State
Country
Australia
Zip Code
4006
Elliott, Suzanne L; Suhrbier, Andreas; Miles, John J et al. (2008) Phase I trial of a CD8+ T-cell peptide epitope-based vaccine for infectious mononucleosis. J Virol 82:1448-57
Elliott, S L; Pye, S J; Schmidt, C et al. (1997) Dominant cytotoxic T lymphocyte response to the immediate-early trans-activator protein, BZLF1, in persistent type A or B Epstein-Barr virus infection. J Infect Dis 176:1068-72
Thomson, S A; Elliott, S L; Sherritt, M A et al. (1996) Recombinant polyepitope vaccines for the delivery of multiple CD8 cytotoxic T cell epitopes. J Immunol 157:822-6
Moss, D J; Schmidt, C; Elliott, S et al. (1996) Strategies involved in developing an effective vaccine for EBV-associated diseases. Adv Cancer Res 69:213-45
Rowe, M; Khanna, R; Jacob, C A et al. (1995) Restoration of endogenous antigen processing in Burkitt's lymphoma cells by Epstein-Barr virus latent membrane protein-1: coordinate up-regulation of peptide transporters and HLA-class I antigen expression. Eur J Immunol 25:1374-84
Scalzo, A A; Elliott, S L; Cox, J et al. (1995) Induction of protective cytotoxic T cells to murine cytomegalovirus by using a nonapeptide and a human-compatible adjuvant (Montanide ISA 720). J Virol 69:1306-9
Thomson, S A; Khanna, R; Gardner, J et al. (1995) Minimal epitopes expressed in a recombinant polyepitope protein are processed and presented to CD8+ cytotoxic T cells: implications for vaccine design. Proc Natl Acad Sci U S A 92:5845-9
Silins, S L; Sculley, T B (1995) Burkitt's lymphoma cells are resistant to programmed cell death in the presence of the Epstein-Barr virus latent antigen EBNA-4. Int J Cancer 60:65-72
McKie, E A; Ubukata, E; Hasegawa, S et al. (1995) The transcripts from the sequences flanking the short component of Marek's disease virus during latent infection form a unique family of 3'-coterminal RNAs. J Virol 69:1310-4
Khanna, R; Burrows, S R; Moss, D J (1995) Immune regulation in Epstein-Barr virus-associated diseases. Microbiol Rev 59:387-405

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