Identification of CTL epitopes in hepatitis C virus by a genome-wide computational scanning and a rational design of peptide vaccine.
Developing a peptide-based vaccine for the highly variable hepatitis C virus (HCV) remains a challenging task. Variant viruses not only escape antigen presentation but also persist in a patient as quasi-species. Such variants are often antagonistic to the responding T cell repertoire. To overcome these problems, we herein propose a cocktail vaccine consisting of a few epitope peptides, which make it possible to outpace the emergence of variant viruses. To design such a vaccine, we developed a way to identify HLA-A*2402-binding peptides efficiently by means of the computational scanning of the whole genome of the pathogen. Most of the predicted peptides exhibited strong binding to the HLA-A*2402 molecule, while also inducing CD8 T cell responses from the patients' peripheral blood mononuclear cells (PBMCs). Peptide-induced T cells were capable of lysing HCV-expressing HepG2 cells which process antigens endogenously. The amount of HCV core antigen in the patients' livers suggested that the lytic activity of the peptide-induced T cells was clearly in a range suitable for therapeutic use. If T cells were activated under optimal conditions by high density peptides, then they tended to be relatively tolerant of single amino acid variations for cytolysis. Finally, an analysis of the viral population isolated in Japan suggested no obvious changes due to immune evasion in the viral genome even in a host population highly biased toward HLA-A*2402.
Mashiba
Toshie
T
Department of Gastroenterology and Metabology, Graduate School of Medicine, Ehime University, Toh-on, Ehime, Japan.
Udaka
Keiko
K
Hirachi
Yasuko
Y
Hiasa
Yoichi
Y
Miyakawa
Tomoya
T
Satta
Yoko
Y
Osoda
Tsutomu
T
Kataoka
Sayo
S
Kohara
Michinori
M
Onji
Morikazu
M
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003198:Computer Simulation; D003600:Cytosol / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D016678:Genome / Q000276:immunology*; D015234:HLA-A Antigens / Q000737:chemistry; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007564:Japan; D008969:Molecular Sequence Data; D010802:Phylogeny; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D022223:Vaccines, Subunit / Q000235:genetics* / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D022223:Vaccines, Subunit