International Immunology, Vol. 12, No. 9, 1293-1302,
September 2000
© 2000 Japanese Society for Immunology
Creating HIV-1 reverse transcriptase cytotoxic T lymphocyte target structures by HLA-A2 heavy chain modifications
Department of Immunology and Institute of Medical Science, University of Toronto, Medical Sciences Building, 1 King's College Circle, Ontario M5S 1A8, Canada
1 Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, V6T 1Z1, Canada
2 Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK
Correspondence to: B. H. Barber
Vigorous HIV-1-specific CD8+ cytotoxic T lymphocyte (CTL) responses play an important role in the control of HIV-1 replication and the induction of a strong, broadly cross-reactive CTL response remains an important goal of HIV vaccine development. It is known that the display of high levels of class I MHC–viral peptide complexes at the cell surface of target cells is necessary to elicit a strong CTL response. We now report two strategies to enhance the presentation of defined HIV-1 epitope-specific CTL target structures, by incorporating subdominant HIV-1 reverse transcriptase (RT) CTL epitope sequences into the human class I MHC molecule HLA-A2. We show that either incorporation of HIV-1 CTL epitopes into the signal sequence of HLA or tethering of epitopes to the HLA-A2 heavy chain provide simple ways to create effective CTL target structures that can be recognized and lysed by human HLA-A2-restricted RT-specific CD8+ CTL. Moreover, cells expressing these epitope-containing HLA-A2 constructs stimulated the generation of primary epitope-specific CTL in vitro. These strategies offer new options in the design of plasmid DNA-based vaccines or immunotherapeutics for the induction of CTL responses against subdominant HIV-1 epitopes.
Keywords: cytotoxic T lymphocyte, HIV-1 HLA-A2, reverse transcriptase, subdominant epitopes
Transmitting editor: A. McMichael
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