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In Vivo Priming Of HIV-Specific CTLs Determines Selective Cross-Reactive Immune Responses Against Poorly Immunogenic HIV-Natural Variants¹

Alexandre Boissonnas^*, Olivia Bonduelle^*, Ariane Antzack^*, Yu-Chun Lone, Cécile Gache^*, Patrice Debre^*, Brigitte Autran^* and Behazine Combadière^2,*

^* Faculté de Medecine Pitié Salpétrière, Laboratoire d’Immunologie Cellulaire, Unité 543, and Unité de Recombinaison et Expression Génétique, Unité 163, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale, Paris, France

Degeneracy of the TCR repertoire might allow for cross-recognition of epitope variants. However, it is unclear how the first encounter with HIV Ags determines recognition of emerging epitope variants. This question remains crucial in the choice of HIV vaccine sequences given the virus variability. In this study, we individualized nine natural mutations within an HIV-Nef_180–189 epitope selected from several HIV-infected individuals. These variants of Nef_180–189 sequence display slightly different HLA-A2 binding capacities and stabilities and we have shown that only two induced a strong CTL response in vivo in HLA-A2 transgenic mice after a single injection. We demonstrated that priming with these two immunogenic variants generated a specific pattern of cross-reactive CTL repertoire directed against poorly immunogenic peptides. Thus, the range of peptide variants recognized by HIV-specific CTL depends upon the Ag encountered during primary immunization of CD8 lymphocytes. These data have practical implications in the development of cross-reactive vaccines against HIV.

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