Multiepitopic HLA-A*0201-restricted immune response against hepatitis B surface antigen after DNA-based immunization.
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 D(b) (HHD) mice, which are deficient for mouse MHC class I molecules (beta(2)-microglobulin(-/-) D(b-/-)) and transgenic for a chimeric HLA-A*0201/D(b) molecule covalently bound to the human beta(2)-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.
Loirat
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D
Unité de Recombinaison et Expression Génétique, Institut National de la Santé et de la Recherche Médicale, Unité 163, Institut Pasteur, Paris, France.
Lemonnier
F A
FA
Michel
M L
ML
D000483:Alleles; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015789:HLA-A2 Antigen / Q000235:genetics* / Q000276:immunology*; D006514:Hepatitis B Surface Antigens / Q000276:immunology*; D017325:Hepatitis B Vaccines / Q000235:genetics / Q000276:immunology; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines; D019444:Vaccines, DNA; D014759:Viral Envelope Proteins; D007371:Interferon-gamma