Despite current aggressive treatment protocols based on powerful drug combinations, the incidence of HIV-1 infection is increasing, from already very large numbers, mainly in developing countries that can least afford these newer drug regimens. The objective of this proposal combines the technologies of T cell immunobiology and synthetic peptide chemistry in a strategy of antigen discovery and optimization to identify individual candidate peptide sequence mimics for HIV-1 gag protein fragments as starting points in the design of preventive and therapeutic vaccines. Individual lines and clones of human cytotoxic T lymphocytes (CTL) having relevant lytic specificity for HIV peptide pulsed target cells will be used to screen very large combinatorial peptide libraries for peptide sequences that best stimulate proliferative, cytokine release, or lytic responses by these CTL clones. Candidate sequences deduced from each clonal scan will be synthesized and each individually assessed for activity on the selecting clone. The most effective peptide sequences will then be made available for ex vivo immunogenicity assessments and for phase I/II toxicity/efficacy clinical trials. Preliminary studies indicate that these library scans identify peptides several orders of magnitude more effective than native peptide ligands used to generate a particular T cell clone, and that these optimized superagonist peptides are effective as vaccines, provoking strong T cell mediated immune responses against native peptide ligands.
Not Available
| Kan-Mitchell, June; Bajcz, Melissa; Schaubert, Keri L et al. (2006) Degeneracy and repertoire of the human HIV-1 Gag p17(77-85) CTL response. J Immunol 176:6690-701 |
