In vivo hierarchy of immunodominant and subdominant HLA-A*0201-restricted T-cell epitopes of HBx antigen of hepatitis B virus.
A polyepitopic CD8+ T-cell response is critical for the control of hepatitis B virus (HBV) infection. The HBV X protein (HBx) is a multifunctional protein that is important for the viral life cycle and for host-virus interactions. The aim of this study was to analyze the immunogenicity and dominance of various HLA-A*0201-restricted HBx-derived epitopes. For this purpose, we immunized HLA-A*0201-transgenic mice with HBx-derived peptides and DNA. This is a powerful model for studying the induction of HLA-A*0201-restricted immune responses in vivo, as these mice possess a cytotoxic T lymphocyte (CTL) repertoire representative of HLA-A2.1 individuals. We used cytotoxic tests and enzyme-linked immunosorbent spot (ELISPOT) assays to study the induction of specific cytotoxic and interferon (IFN)-gamma-secreting T cells. This allowed us to classify the HBx epitopes according to their T-cell activation capacity. After endogenous processing of the antigen synthesized in vivo after DNA-based immunization, we found that the HBx-specific T-cell response is targeted against one immunodominant epitope. Furthermore, following peptide immunization, we identified six additional novel subdominant T-cell epitopes. Inclusion of well-characterized epitopic sequences of HBx in a new vaccine for chronic HBV infections could help to broaden the T-cell response.
Malmassari
Silvina
S
Institut National de la Santé et de la Recherche Médicale, Unité 370, Institut Pasteur, Unité carcinogenèse hépatique et virologie moléculaire, Département de médecine moléculaire, 28, rue du Dr. Roux, 75724 Paris cedex 15, France.
Lone
Yu Chun
YC
Zhang
Menghua
M
Transy
Catherine
C
Michel
Marie-Louise
ML
D000595:Amino Acid Sequence; D000818:Animals; D004279:DNA, Viral / Q000008:administration & dosage / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D005260:Female; D015234:HLA-A Antigens / Q000378:metabolism*; D015789:HLA-A2 Antigen; D006515:Hepatitis B virus / Q000276:immunology*; D007114:Immunization; D016056:Immunodominant Epitopes / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D010957:Plasmids / Q000008:administration & dosage; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D054334:Viral Regulatory and Accessory Proteins
D004279:DNA, Viral; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D010455:Peptides; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D007371:Interferon-gamma