Human T-cell responses to HLA-A-restricted high binding affinity peptides of human papillomavirus type 18 proteins E6 and E7.
Human Papillomaviruses (HPVs) are sexually transmitted pathogens, which are implicated in the etiology of cervical cancer. The early proteins E6 and E7 of HPV have transforming capacity and interfere with the cell cycle control of infected host cells and are essential for the maintenance of the transformed state. Identification of MHC class I-restricted, immunogenic peptides derived from either the E6 or the E7 protein is essential for the design of vaccines as well as the monitoring of clinical trials and immunotherapeutic approaches for the treatment of HPV-18-induced carcinomas. We have determined the binding affinities for all possible 9-mer peptides spanning the entire E6 and E7 amino acid sequence for the HLA-A*0101, HLA-A*0201, HLA-A*0302, HLA-A*1102, and HLA-A*2402101 molecules by a competition assay with reference peptides, thereby establishing the binding peptides as potential cytotoxic T-cell epitopes. From the HLA-A*0201 binding peptides, we selected five E6-derived and one E7-derived peptide with high affinities for HLA-A*0201. These six peptides were tested for their immunogenicity by in vitro immunization assays with purified human CD8+ T cells. We identified three HPV-18 E6-derived peptides (ELTEVFEFA, KTVLELTEV, and KLPDLCTEL) and the E7-derived peptide TLQDIVLHL to be highly immunogenic. Overall, these results will help to design vaccines for the prevention or treatment of HPV-18-induced cervical cancer.
Rudolf
M P
MP
Cardinal Bernardin Cancer Center, Loyola University of Chicago, Maywood, Illinois 60153, USA.
Man
S
S
Melief
C J
CJ
Sette
A
A
Kast
W M
WM
D000596:Amino Acids / Q000737:chemistry; D001667:Binding, Competitive; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002277:Carcinoma / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins; D000939:Epitopes / Q000737:chemistry; D005260:Female; D005805:Genes, MHC Class I; D015234:HLA-A Antigens / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011485:Protein Binding; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000628:therapy
D000596:Amino Acids; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D000939:Epitopes; D015234:HLA-A Antigens; D009856:Oncogene Proteins, Viral; D010455:Peptides