TY - JOUR

T1 - Human leukocyte antigen (HLA) class I restricted epitope discovery in yellow fewer and dengue viruses

T2 - importance of HLA binding strength

AU - Lund, Ole

AU - Nascimento, Eduardo J M

AU - Maciel, Milton

AU - Nielsen, Morten

AU - Larsen, Mette Voldby

AU - Lundegaard, Claus

AU - Harndahl, Mikkel

AU - Lamberth, Kasper

AU - Buus, Søren

AU - Salmon, Jérôme

AU - August, Thomas J

AU - Marques, Ernesto T A

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Animals

KW - Dengue Virus

KW - Enzyme-Linked Immunosorbent Assay

KW - Epitopes

KW - Histocompatibility Antigens Class I

KW - Humans

KW - Mice

KW - Mice, Transgenic

KW - Molecular Sequence Data

KW - Yellow Fever Vaccine

KW - Yellow fever virus

U2 - 10.1371/journal.pone.0026494

DO - 10.1371/journal.pone.0026494

M3 - Journal article

C2 - 22039500

VL - 6

SP - e26494

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 10

ER -