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Human leukocyte antigen (HLA) class I restricted epitope discovery in yellow fewer and dengue viruses: importance of HLA binding strength.

Lund O, Nascimento EJ, Maciel M, Nielsen M, Larsen MV, Lundegaard C, Harndahl M, Lamberth K, Buus S, Salmon J, August TJ, Marques ET - PLoS ONE (2011)

Bottom Line: 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 immunogenic peptides bound HLA significantly stronger than the non-immunogenic peptides.The results indicate the importance of the strength of HLA binding in shaping the immune response.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark. lund@cbs.dtu.dk

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.

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Related in: MedlinePlus

Schematic diagram of the epitope discovery scheme.In addition to the 237 good binders, 5 weak binders and one non-binder was also tested in this study for comparison, but these are not included in the figure.
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pone-0026494-g001: Schematic diagram of the epitope discovery scheme.In addition to the 237 good binders, 5 weak binders and one non-binder was also tested in this study for comparison, but these are not included in the figure.

Mentions: 158 DENV peptides, which together represents all four serotypes and cover the 12 HLA-I supertypes were selected using same procedure as for the YFV epitopes. 147 were synthesized and 116 (79%) were found to bind with a KD below 500 nM. A schematic diagram of the selection scheme is shown in figure 1.


Human leukocyte antigen (HLA) class I restricted epitope discovery in yellow fewer and dengue viruses: importance of HLA binding strength.

Lund O, Nascimento EJ, Maciel M, Nielsen M, Larsen MV, Lundegaard C, Harndahl M, Lamberth K, Buus S, Salmon J, August TJ, Marques ET - PLoS ONE (2011)

Schematic diagram of the epitope discovery scheme.In addition to the 237 good binders, 5 weak binders and one non-binder was also tested in this study for comparison, but these are not included in the figure.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198402&req=5

pone-0026494-g001: Schematic diagram of the epitope discovery scheme.In addition to the 237 good binders, 5 weak binders and one non-binder was also tested in this study for comparison, but these are not included in the figure.
Mentions: 158 DENV peptides, which together represents all four serotypes and cover the 12 HLA-I supertypes were selected using same procedure as for the YFV epitopes. 147 were synthesized and 116 (79%) were found to bind with a KD below 500 nM. A schematic diagram of the selection scheme is shown in figure 1.

Bottom Line: 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 immunogenic peptides bound HLA significantly stronger than the non-immunogenic peptides.The results indicate the importance of the strength of HLA binding in shaping the immune response.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark. lund@cbs.dtu.dk

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.

Show MeSH
Related in: MedlinePlus