AEGiS-13IAC: Evaluation of the immunogenic potential of HIV derived epitopes using an HLA-B*0702+/+ H-2Kb-/- H-2Db-/- strain of mouse.

13th International AIDS Conference

Durban, South Africa - July 9-July 14, 2000

Evaluation of the immunogenic potential of HIV derived epitopes using an HLA-B*0702+/+ H-2Kb-/- H-2Db-/- strain of mouse.

Int Conf AIDS 2000 Jul 9-14; 13:(abstract no. TuOrA291)

Cardinaud S, Rohrlich P, Langlade-Demoyen P, Firat H, Lemonnier F
S. Cardinaud, Institut Pasteur, Unite d'Immunite Cellulaire Antivirale, Dpt SIDA & Retrovirus, 28, rue du Dr Roux, 75724 Paris Cedex 15, France, Tel.: +33 1 45 68 88 63, Fax: +33 1 45 68 88 64, E-mail: cardinau@pasteur.fr

BACKGROUND: It is conceivable that a rapid recruitment and expansion of specific HIV cytotoxic T cells (CTL) after exposure play an important role in protection against HIV infection. We have generated H2-class I negative HLA-B*0702 transgenic mice and used them for comparative evaluation of the immunogenecity of potential peptide based vaccines.

METHODS: C57Bl/6 transgenic mice, expressing a chimeric alpha chain of the major histocompatibility complex class I, B7B7Kd (human alpha 1 and alpha 2 domains), have been deleted from their genes coding H-2Kb and H-2Db molecules. The CD8+ cells expression and the diversity of their V beta molecule repertoire were assessed by immunofluorescence. Mice have been immunized in incompleted Freund's adjuvant, adding helper peptide (HBVc128.140), against 7 peptides derived from p24, gp41, RT, and nef proteins, previously described as immunogenic in HLA-B7 patients (6 mice per peptide). The specific cytolytic activity of splenocytes was then assessed.

RESULTS: A substantial number of CD8+ cells in the transgenic mice was observed (20% of peripheral mononuclear cells). T cell repertoire was diversified in terms of V beta, suggesting an efficient T cell education at the thymic level at the contact of the transgenic molecule. Immunizing transgenic B7B7Kd mice with HIV derived peptides led us to establish a hierarchy: among 7 peptides, 5 induced specific cytolytic responses with interindividual differences according to the peptide in terms of number of responding mice (20% to 100%) and in terms of the percentage of specific lysis (10% to 57%). A parallel study of the CTL responses of H2-class I positive B7B7Kd+/+ transgenic mice illustrates the improved capacity of H2-class I negative B7B7Kd+/+ mice to develop HLA-B7 restricted CTL responses (p = 0.05).

CONCLUSIONS: HLA-B*0702+/+ H-2Kb-/- H-2Db-/- strain of mouse is an useful animal model for an evaluation of the immunogenic potential of HIV derived epitopes. This strain should unable us to compare different immunization strategies and to identify new HLA-B*0702 restricted epitopic peptides as well as to optimize the immunogenecity of subdominant peptides.

Keywords: AEGIS, H-2 Antigens, Epitopes, HIV, T-Lymphocytes, Cytotoxic, Mice, Transgenic, CD8-Positive T-Lymphocytes, HLA-B7 Antigen, Peptides, Major Histocompatibility Complex, Mice, Knockout, H-2k(b) antigen, Mice, Animal, Human, immunology, genetics
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TuOrA291