title: Human leukocyte antigen (HLA) class I restricted epitope discovery in yellow fewer and dengue viruses: importance of HLA binding strength.
abstract: Epitopes from all available full-length sequences of yellow fever virus (YFV) and dengue fever virus (DENV) restricted by Human Leukocyte Antigen class I (HLA-I) alleles covering 12 HLA-I supertypes were predicted using the NetCTL algorithm. A subset of 179 predicted YFV and 158 predicted DENV epitopes were selected using the EpiSelect algorithm to allow for optimal coverage of viral strains. The selected predicted epitopes were synthesized and approximately 75% were found to bind the predicted restricting HLA molecule with an affinity, K(D), stronger than 500 nM. The immunogenicity of 25 HLA-A*02:01, 28 HLA-A*24:02 and 28 HLA-B*07:02 binding peptides was tested in three HLA-transgenic mice models and led to the identification of 17 HLA-A*02:01, 4 HLA-A*2402 and 4 HLA-B*07:02 immunogenic peptides. The immunogenic peptides bound HLA significantly stronger than the non-immunogenic peptides. All except one of the immunogenic peptides had K(D) below 100 nM and the peptides with K(D) below 5 nM were more likely to be immunogenic. In addition, all the immunogenic peptides that were identified as having a high functional avidity had K(D) below 20 nM. A*02:01 transgenic mice were also inoculated twice with the 17DD YFV vaccine strain. Three of the YFV A*02:01 restricted peptides activated T-cells from the infected mice in vitro. All three peptides that elicited responses had an HLA binding affinity of 2 nM or less. The results indicate the importance of the strength of HLA binding in shaping the immune response.
authors: Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark. lund@cbs.dtu.dk
authors: Ole
authors: O
authors: Lund
authors: Eduardo J M
authors: EJ
authors: Nascimento
authors: Milton
authors: M
authors: Maciel
authors: Morten
authors: M
authors: Nielsen
authors: Mette Voldby
authors: MV
authors: Larsen
authors: Claus
authors: C
authors: Lundegaard
authors: Mikkel
authors: M
authors: Harndahl
authors: Kasper
authors: K
authors: Lamberth
authors: Søren
authors: S
authors: Buus
authors: Jérôme
authors: J
authors: Salmon
authors: Thomas J
authors: TJ
authors: August
authors: Ernesto T A
authors: ET
authors: Marques
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003716:Dengue Virus / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D022341:Yellow Fever Vaccine / Q000276:immunology; D015005:Yellow fever virus / Q000276:immunology*
chemical_list: D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D022341:Yellow Fever Vaccine