Creating HIV-1 reverse transcriptase cytotoxic T lymphocyte target structures by HLA-A2 heavy chain modifications.
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.
Dela Cruz
C S
CS
Department of Immunology and Institute of Medical Science, University of Toronto, Medical Sciences Building, 1 King's College Circle, Ontario M5S 1A8, Canada.
Tan
R
R
Rowland-Jones
S L
SL
Barber
B H
BH
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D000939:Epitopes / Q000276:immunology; D005434:Flow Cytometry; D005822:Genetic Vectors; D054303:HIV Reverse Transcriptase / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000032:analysis / Q000276:immunology*; D006801:Humans; D021382:Protein Sorting Signals / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014170:Transformation, Genetic
D000939:Epitopes; D015789:HLA-A2 Antigen; D021382:Protein Sorting Signals; D054303:HIV Reverse Transcriptase