T-cell Responses in Individuals Infected with Zika Virus and in Those Vaccinated Against Dengue Virus
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Abstract
Background: The outbreak of Zika virus (ZIKV) infection in Brazil has raised concerns that infection during pregnancy could cause microcephaly and other severe neurodevelopmental malformations in the fetus. The mechanisms by which ZIKV causes fetal abnormalities are largely unknown. The importance of pre-infection with dengue virus (DENV), or other flaviviruses endemic to Brazil, remains to be investigated. It has been reported that antibodies directed against DENV can increase ZIKV infectivity by antibody dependent enhancement (ADE), suggesting that a history of prior DENV infection might worsen the outcome of ZIKV infection.
Methods: We used bioinformatics tools to design 18 peptides from the ZIKV envelope containing predicted HLA-I T-cell epitopes and investigated T-cell cross-reactivity between ZIKV-infected individuals and DENV-vaccinated subjects by IFNg ELISPOT.
Results: Three peptides induced IFNg production in both ZIKV-infected subjects and in DENV-vaccinated individuals. Flow cytometry indicated that 1 ZIKV peptide induced a CD4+ T-cell response in DENV-vaccinated subjects.
Conclusions: We demonstrated that vaccination against DENV induced a T-cell response against ZIKV and identified one such CD4+ T-cell epitope. The ZIKV-reactive CD4+ T cells induced by DENV vaccination and identified in this study could contribute to the appearance of cross-reactive antibodies mediating ADE.
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Figure legends
Figure 1. Alignment of ZIKV and DENV Sequences. The ZIKV amino acid sequences of selected peptides were aligned to the corresponding DENV-1, DENV-2, DENV-3, and DENV-4 sequences using EMBL-EBI bioinformatics framework. * indicates positions with a single, fully conserved residue; : indicates conservation between groups of strongly similar properties—roughly equivalent to scoring > 0.5 in the Gonnet PAM 250 matrix; . indicates conservation between groups of weakly similar properties—roughly equivalent to scoring ≤ 0.5 and > 0 in the Gonnet PAM 250 matrix.
Figure 2. Identification of ZIKV Epitope. PBMCs from ZIKV-infected subjects were stimulated with peptides 1-18 and IFNg production was evaluated by ELISPOT. The dashed line represents the background level of IFNg in the absence of stimulation multiplied by 2.
Figure 3. Identification of DENV-ZIKV Cross-reactive Peptides. PBMCs from DENV-vaccinated subjects were stimulated with peptides 1-18 and IFNg production was evaluated by ELISPOT. The dashed line represents the background level of IFNg in the absence of stimulation multiplied by 2.
Figure 4. Fine Mapping of Peptide 1. IFNg spots per million PBMCs after stimulation with peptides 1, A, B, and C for DENV 1038 and 1049. The dashed line represents the background level of IFNg in the absence of stimulation multiplied by 2 (A). CellTrace Violet labeled PBMCs were stimulated for 6 days with peptide 1 in the presence of IL-2 (20 U/ml) before re-stimulation with peptide 1 for 12 hours in the presence of monensin. As a negative control, PBMCs were cultured with IL-2 in absence of peptide stimulation. Cells were then stained for CD3, CD4, CD8, and IFNγ. Representative flow plots (B).