Several lines of evidence implicate CD8 cytotoxic T lymphocytes (CTL) in protective immune responses against HIV. CTLs recognize short viral peptide epitopes in association with HLA class I molecules on virus-infected cells. Unfortunately, due to the presence of many alleles in the human population, each individual tends to """"""""present"""""""" different viral peptides to CD8 lymphocytes. This proposal focuses on a group of HLA-B class alleles termed the HLA-B7, B55, B53, B35, B54, B56, B67, and B78. The HLA B-7 supertype covers approximately 49% of the population, and those alleles tend to bind identical viral peptide epitopes. A group of HIV CCTL epitopes that were defined in HIV-infected individuals in association with one or more of the B7 supertype alleles has been selected for study here. (1) The binding of this group of epitopes to different B7 supertypes will be examined. A maximum of four distinct epitopes will be selected on the basis of their ability to bind a to multiple B7 supertype alleles for further study. (2) The selected HLA-B7 supertype-binding HIV epitopes will be examined for their ability to elicit CTL responses in vitro in human CD8 T lymphocytes from uninfected donors expressing different B7 supertype alleles. The CTLs generated against the optimal B7 supertype-restricted HIV CTL epitopes in (2) will be examined for (3) their ability to recognize endogenously generated epitopes in virus-infected cells and inhibit HIV infection in vitro, and for (4) their ability to recognize viral variant epitopes. Collectively, these studies will strive to define one or more HIV CTL epitopes that are immunogenic with multiple B7 supertype alleles and that induce cross-recognition of other HIV strains. Thus, these studies will provide the foundation for the inclusion of cross reactive, B7 supertype-restricted HIV CTL epitopes in new vaccine approaches.
