Abstract

Our long-term aim is to provide an in-depth understanding of the relationship between Epstein-Barr virus (EBV) and human disease as a basis of formulating an intervention strategy. Compelling evidence has demonstrated that EBV persists for life following primary infection and is controlled by EBV-specific cytotoxic T lymphocytes (CTLs). Disruption of this delicate balance between virus and host results in an expansion of virus-infected cells which may contribute to a spectrum of clinical disorders including malignancy. The theme of this proposal is to exploit our expertise in the mapping of CTL epitopes and in EBV strain variation to establish a frame of reference to developing a vaccine capable of preventing EBV-associated diseases. Specifically, we propose to: (1)identify the dominant and secondary EBV CTL epitopes using procedures already in use in our laboratories. The techniques involved include T-cell colony formation, Cr release assay, site directed mutagenesis and gene targeting of proteins in transformation and T-cell recognition. (2)determine the extent of EBV strain variation, in particular the variation associated with CTL epitopes. (3)to define the importance of CTL epitopes in the recognition of associated tumors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA052250-03
Application #
3197062
Study Section
Special Emphasis Panel (SRC (51))
Project Start
1990-07-01
Project End
1993-06-30
Budget Start
1992-09-30
Budget End
1993-06-30
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Queensland Institute of Medical Research
Department
Type
DUNS #
758815328
City
Herston
State
Country
Australia
Zip Code
4006

  Publications

Khanna, R; Cooper, L; Kienzle, N et al. (1997) Engagement of CD40 antigen with soluble CD40 ligand up-regulates peptide transporter expression and restores endogenous processing function in Burkitt's lymphoma cells. J Immunol 159:5782-5
Khanna, R; Burrows, S R; Burrows, J M (1997) The role of cytotoxic T lymphocytes in the evolution of genetically stable viruses. Trends Microbiol 5:64-9
Khanna, R; Burrows, S R; Steigerwald-Mullen, P M et al. (1997) Targeting Epstein-Barr virus nuclear antigen 1 (EBNA1) through the class II pathway restores immune recognition by EBNA1-specific cytotoxic T lymphocytes: evidence for HLA-DM-independent processing. Int Immunol 9:1537-43
Khanna, R; Burrows, S R; Thomson, S A et al. (1997) Class I processing-defective Burkitt's lymphoma cells are recognized efficiently by CD4+ EBV-specific CTLs. J Immunol 158:3619-25
Burrows, S R; Silins, S L; Cross, S M et al. (1997) Human leukocyte antigen phenotype imposes complex constraints on the antigen-specific cytotoxic T lymphocyte repertoire. Eur J Immunol 27:178-82
Khanna, R; Burrows, S R; Neisig, A et al. (1997) Hierarchy of Epstein-Barr virus-specific cytotoxic T-cell responses in individuals carrying different subtypes of an HLA allele: implications for epitope-based antiviral vaccines. J Virol 71:7429-35
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
Burrows, J M; Burrows, S R; Poulsen, L M et al. (1996) Unusually high frequency of Epstein-Barr virus genetic variants in Papua New Guinea that can escape cytotoxic T-cell recognition: implications for virus evolution. J Virol 70:2490-6
Burrows, J M; Khanna, R; Sculley, T B et al. (1996) Identification of a naturally occurring recombinant Epstein-Barr virus isolate from New Guinea that encodes both type 1 and type 2 nuclear antigen sequences. J Virol 70:4829-33
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

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