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The Journal of Immunology, 2000, 165: 4748-4755.
Copyright © 2000 by The American Association of Immunologists

Multiepitopic HLA-A*0201-Restricted Immune Response Against Hepatitis B Surface Antigen After DNA-Based Immunization

Delphine Loirat1,*,{dagger}, François A. Lemonnier{ddagger} and Marie-Louise Michel2,*

* Unité de Recombinaison et Expression Génétique, Institut National de la Santé et de la Recherche Médicale, Unité 163, Institut Pasteur, Paris, France; {dagger} IDM, Immuno-Designed Molecules, Paris, France; and {ddagger} Unité d’Immunité Cellulaire Antivirale, Institut Pasteur, Paris, France

CTL together with anti-envelope Abs represent major effectors for viral clearance during hepatitis B virus (HBV) infection. The induction of strong cytotoxic and Ab responses against the envelope proteins after DNA-based immunization has been proposed as a promising therapeutic approach to mediate viral clearance in chronically infected patients. Here, we studied the CTL responses against previously described hepatitis B surface Ag (HBsAg)-HLA-A*0201-restricted epitopes after DNA-based immunization in HLA-A*0201 transgenic mice. The animal model used was Human Human Db (HHD) mice, which are deficient for mouse MHC class I molecules (ß2-microglobulin-/- Db-/-) and transgenic for a chimeric HLA-A*0201/Db molecule covalently bound to the human ß2-microglobulin (HHD+/+). Immunization of these mice with a DNA vector encoding the small and the middle HBV envelope proteins carrying HBsAg induced CTL responses against several epitopes in each animal. This study performed on a large number of animals described dominant epitopes with specific CTL induced in all animals and others with a weaker frequency of recognition. These results confirmed the relevance of the HHD transgenic mouse model in the assessment of vaccine constructs for human use. Moreover, genetic immunization of HLA-A2 transgenic mice generates IFN-{gamma}-secreting CD8+ T lymphocytes specific for endogenously processed peptides and with recognition specificities similar to those described during self-limited infection in humans. This suggests that responses induced by DNA immunization could have the same immune potential as those developing during natural HBV infection in human patients.




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