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Extension of HLA-A*0201-Restricted Minimal Epitope by N-Palmitoyl-lysine Increases the Life Span of Functional Presentation to Cytotoxic T Cells¹

Estelle Loing^2,*, Muriel Andrieu^3,, Kader Thiam^3,*, Dominik Schörner, Karl-Heinz Wiesmüller, Anne Hosmalin, Günther Jung and Hélène Gras-Masse^*

^* Unité Mixte de Recherche 8525, Centre National de la Recherche Scientifique-Lille II University and Institut Pasteur de Lille, Lille, France; Institut National de la Santé et de la Recherche Médicale Unité 445, Institut Cochin de Génétique Moléculaire, Paris, France; and Institut für Organische Chemie, Universität Tübingen, Tübingen, Germany

The delineation of the minimal requirements for efficient delivery of functional cytotoxic epitopes into APC could be a step toward the definition of "minimal length" lipopeptides for the modulation of CTL activity. Several analogues of the HLA-A*0201-restricted HIV-1 polymerase (pol_476–484) minimal cytotoxic epitope were obtained by modifying P0, P1, or P10 positions by a single N-palmitoyl-lysine residue. The use of fluorescent derivatives confirmed the cell-permeating activities and suggested that a P0- and a P1-modified lipopeptide possessing ionizable extremities fulfills the structural requirements for MHC loading. The expressions of HLA-peptide complexes at the surface of TAP-deficient cells incubated with the parent epitope or lipopeptide derivatives were compared, in terms of intensity and stability. Both lipopeptides induced a considerably prolonged expression of conformationally correct complexes, which were dependent on the integrity of the exocytosis pathway, suggesting a dynamic mechanism of formation or reloading of the complexes from an intracellular pool. The agonistic activities of the different HLA-peptide complexes were evaluated using two independent T cell lines from HIV-infected donors. We report that a lipodecapeptide obtained by N-terminal addition of a N-palmitoyl-lysine to the pol_476–484 epitope was able to increase the life span of functional presentation to cytotoxic T cells specific for the parent peptide.

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