Immunogenically optimized peptides derived from natural mutants of HIV CTL epitopes and peptide combinatorial libraries.
Two strategies were aimed at identifying immunogenically optimized peptides for the potential use in the formulation of an effective prophylactic or therapeutic HIV-1 vaccine. Three CTL epitopes were investigated: Gag p24(19-27) TV9, Gag p17(77-85) SL9, and RT(309-317) IV9. The first strategy derives from the hypothesis that a number of rare mutant CTL epitopes of HIV-1 may be more immunogenic than the common ones. As such, these rare mutant sequences might be highly effective in generating cross reactive anti-HIV-1 CTL responses against a range of mutant sequences. As anticipated, several rare mutant peptide sequences were identified that generated strong CTL responses against both the consensus sequences and several naturally occurring mutants in human PBL cultures primed ex vivo and in HLA-A2 transgenic mice immunized in vivo. Finally, to reach beyond the sequence diversity of the "natural" library of mutated sequences, a synthetic combinatorial peptide library was screened with a TV9 specific T-cell line; this resulted in the identification of an immunogenically optimized mimic peptide sequence that provoked highly effective CTL immune responses against TV9 and mutants. Sequence homologies between the natural mutants and synthetic mimic may provide insight into key contact positions in the MHC/TCR/peptide complex.
Blondelle
Sylvie E
SE
Mixture Sciences, Inc., 3550 General Atomics Ct, San Diego, CA 92121, USA. sylvieb@burnham.org
Moya-Castro
Rosa
R
Osawa
Keiko
K
Schroder
Kim
K
Wilson
Darcy B
DB
D000818:Animals; D019380:Anti-HIV Agents / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D020650:Combinatorial Chemistry Techniques; D003429:Cross Reactions / Q000235:genetics / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006678:HIV / Q000235:genetics / Q000276:immunology*; D016655:HIV Core Protein p24 / Q000235:genetics / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018716:Molecular Mimicry; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D019151:Peptide Library; D010455:Peptides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000502:physiology*
D019380:Anti-HIV Agents; D018984:Epitopes, T-Lymphocyte; D016655:HIV Core Protein p24; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D019151:Peptide Library; D010455:Peptides; D054299:env Gene Products, Human Immunodeficiency Virus; D054301:gag Gene Products, Human Immunodeficiency Virus; C473991:p17 gag peptide, human immunodeficiency virus