In vivo priming of HIV-specific CTLs determines selective cross-reactive immune responses against poorly immunogenic HIV-natural variants.
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.
Boissonnas
Alexandre
A
Faculté de Medecine Pitié Salpétrière, Laboratoire d'Immunologie Cellulaire, Unité 543, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale, Paris, France.
Bonduelle
Olivia
O
Antzack
Ariane
A
Lone
Yu-Chun
YC
Gache
Cécile
C
Debre
Patrice
P
Autran
Brigitte
B
Combadière
Behazine
B
D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D000818:Animals; D002460:Cell Line; D003429:Cross Reactions / Q000235:genetics; D003601:Cytotoxicity Tests, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology*; D005260:Female; D015693:Gene Products, nef / Q000008:administration & dosage / Q000276:immunology*; D014644:Genetic Variation / Q000276:immunology*; D015488:HIV Antigens / Q000008:administration & dosage / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007279:Injections, Subcutaneous; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000008:administration & dosage / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D014611:Vaccination / Q000379:methods
D018984:Epitopes, T-Lymphocyte; D015693:Gene Products, nef; D015488:HIV Antigens; D015789:HLA-A2 Antigen; D009842:Oligopeptides