Design of a HIV-1-derived HLA-B07.02-restricted polyepitope construct.
OBJECTIVE
To design a vaccine construct containing various but conserved HIV-1-derived epitopes and generating broad CD8 T cell responses.


METHODS
HLA-B7 transgenic H-2KD KO transgenic mice were used to identify potential new HLA-B07.02-restricted HIV-1-derived epitopes. Immunological recognition of these epitopes was confirmed by IFN-gamma ELISpot assays with PBMCs from HLA-B*0702 HIV-1-infected individuals. For these peptides as well as others previously identified, the capacity to induce cross-reactive responses against their frequent allelic variants was evaluated in the mouse model. A set of epitopes inducing strong T cell responses against various and conserved regions of HIV-1 was selected. A DNA vaccine was designed to express them as a unique antigen with or without a three amino acid ARY extension flanking each epitope. The spectrum of CD8 T responses generated by polyepitope constructs was tested in HLA-B7 transgenic mice.


RESULTS
Five new epitopes were identified in accessory and regulatory HIV-1 proteins. Twelve HLA-B07.02-restricted epitopes were selected on the basis of their structural conservation and cross-reactive immunogenicity. The ARY N-terminal extension flanking each epitope markedly increases their affinity for TAP and the use of this flanking extension in polyepitope vaccine has a sizable advantage to induce CD8 T cell cytotoxic responses in mice following DNA immunization.


CONCLUSIONS
The HLA-B7 mouse model allows to rapidly identify various HIV-1-derived epitopes of vaccine interest. Grouped in a polyepitope construct designed to increase their processing, this vaccine may be suitable for inducing multiple and relevant HIV-1-specific CTL responses in humans.
Cardinaud
Sylvain
S
Unité d'Immunité Cellulaire Antivirale, Département d'Immunologie, Institut Pasteur, 25 rue du Dr Roux, Paris Cedex 15, France.
Bouziat
Romain
R
Rohrlich
Pierre-Simon
PS
Tourdot
Sophie
S
Weiss
Laurence
L
Langlade-Demoyen
Pierre
P
Burgevin
Anne
A
Fiorentino
Susana
S
van Endert
Peter
P
Lemonnier
François A
FA
D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology*; D015793:HLA-B7 Antigen; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology
D016915:AIDS Vaccines; D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; C477444:HLA-B*07:02 antigen; D015793:HLA-B7 Antigen; D009842:Oligopeptides; D019444:Vaccines, DNA; C080396:trypsinogen activation peptide