Dataset Information

Conserved epitopes with high HLA-I population coverage are targets of CD8+ T cells associated with high IFN-? responses against all dengue virus serotypes.

ABSTRACT: Cytotoxic CD8+ T cells are key for immune protection against viral infections. The breadth and cross-reactivity of these responses are important against rapidly mutating RNA viruses, such as dengue (DENV), yet how viral diversity affect T cell responses and their cross-reactivity against multiple variants of the virus remains poorly defined. In this study, an integrated analysis was performed to map experimentally validated CD8+ T cell epitopes onto the distribution of DENV genome sequences across the 4 serotypes worldwide. Despite the higher viral diversity observed within HLA-I restricted epitopes, mapping of 609 experimentally validated epitopes sequences on 3985 full-length viral genomes revealed 19 highly conserved epitopes across the four serotypes within the immunogenic regions of NS3, NS4B and NS5. These conserved epitopes were associated with a higher magnitude of IFN-? response when compared to non-conserved epitopes and were restricted to 13 HLA class I genotypes, hence providing high coverage among human populations. Phylogeographic analyses showed that these epitopes are largely conserved in most of the endemic regions of the world, and with only some of these epitopes presenting distinct mutated variants circulating in South America and Asia.This study provides evidence for the existence of highly immunogenic and conserved epitopes across serotypes, which may impact design of new universal T-cell-inducing vaccine candidates that minimise detrimental effects of viral diversification and at the same time induce responses to a broad human population.

SUBMITTER: Adikari TN

PROVIDER: S-EPMC7687909 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Conserved epitopes with high HLA-I population coverage are targets of CD8+ T cells associated with high IFN-γ responses against all dengue virus serotypes.

Adikari Thiruni N TN Di Giallonardo Francesca F Leung Preston P Grifoni Alba A Sette Alex A Weiskopf Daniela D Bull Rowena A RA Luciani Fabio F

Scientific reports 20201124 1

Cytotoxic CD8+ T cells are key for immune protection against viral infections. The breadth and cross-reactivity of these responses are important against rapidly mutating RNA viruses, such as dengue (DENV), yet how viral diversity affect T cell responses and their cross-reactivity against multiple variants of the virus remains poorly defined. In this study, an integrated analysis was performed to map experimentally validated CD8+ T cell epitopes onto the distribution of DENV ...[more]

PMID: 33235334

Similar Datasets

Project description:BACKGROUND: All four dengue virus (DV) serotypes (D1V, D2V, D3V and D4V) can cause a series of disorders, ranging from mild dengue fever (DF) to severe dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). Previous studies have revealed that DV serotype-specific CD8(+) T cells are involved in controlling DV infection. Serotype cross-reactive CD8(+) T-cells may contribute to the immunopathogenesis of DHF/DSS. The aim of the study was to identify HLA-A*0201-binding peptides from four DV serotypes. We then examined their immunogenicity in vivo and cross-reactivity within heterologous peptides. METHODS: D1V-derived candidate CD8(+) T-cell epitopes were synthesized and evaluated for their affinity to the HLA-A*0201 molecule. Variant peptides representing heterologous D2V, D3V, D4V serotypes were synthesized. The immunogenicity of the high-affinity peptides were evaluated in HLA-A*0201 transgenic mice. RESULTS: Of the seven D1V-derived candidate epitopes [D1V-NS4a(56-64)(MLLALIAVL), D1V-C(46-54)(LVMAFMAFL), D1V-NS4b(562-570)(LLATSIFKL), D1V-NS2a(169-177)(AMVLSIVSL), D1V-NS4a(140-148)(GLLFMILTV), D1V-NS2a(144-152)(QLWAALLSL) and D1V-NS4b(183-191)(LLMRTTWAL)], three peptides [D1V-NS4a(140-148), D1V-NS2a(144-152) and D1V-NS4b(183-191)] had a high affinity for HLA-A*0201 molecules. Moreover, their variant peptides for D2V, D3V and D4V [D2V-NS4a(140-148)(AILTVVAAT), D3V-NS4a(140-148)(GILTLAAIV), D4V-NS4a(140-148)(TILTIIGLI), D2V-NS2a(144-152)(QLAVTIMAI), D3V-NS2a(144-152)(QLWTALVSL), D4V-NS2a(143-151)(QVGTLALSL), D2V-NS4b(182-190)(LMMRTTWAL), D3V-NS4b(182-190) (LLMRTSWAL) and D4V-NS4b(179-187)(LLMRTTWAF)] also had a high affinity for HLA-A*0201 molecules. Furthermore, CD8+ T cells directed to these twelve peptides were induced in HLA-A*0201 transgenic mice following immunization with these peptides. Additionally, cross-reactivity within four peptides (D1V-NS4b(183-191), D2V-NS4b(182-190), D3V-NS4b(182-190) and D4V-NS4b(179-187)) was observed. CONCLUSIONS: Two novel serotype-specific HLA-A*0201-restricted CD8(+) T-cell epitopes (NS4a(140-148) and NS2a(144-152)) and one cross-reactive HLA-A*0201-restricted CD8(+) T-cell epitopes which is similar to a previously identified epitope were identified in D1V-D4V. Combining prediction algorithms and HLA transgenic mice is an effective strategy to identify HLA-restricted epitopes. Serotype-specific epitopes would be used to determine the protective role of serotype-specific CD8(+) T cells, while cross-reactive epitopes may provide assistance in exploring the role of serotype cross-reactive CD8(+) T cells in the immunopathogenesis of DHF/DSS.

Project description:UnlabelledThe incidence of infection with any of the four dengue virus serotypes (DENV1 to -4) has increased dramatically in the last few decades, and the lack of a treatment or vaccine has contributed to significant morbidity and mortality worldwide. A recent comprehensive analysis of the human T cell response against wild-type DENV suggested an human lymphocyte antigen (HLA)-linked protective role for CD8(+) T cells. We have collected one-unit blood donations from study participants receiving the monovalent or tetravalent live attenuated DENV vaccine (DLAV), developed by the U.S. National Institutes of Health. Peripheral blood mononuclear cells from these donors were screened in gamma interferon enzyme-linked immunosorbent spot assays with pools of predicted, HLA-matched, class I binding peptides covering the entire DENV proteome. Here, we characterize for the first time CD8(+) T cell responses after live attenuated dengue vaccination and show that CD8(+) T cell responses in vaccinees were readily detectable and comparable to natural dengue infection. Interestingly, whereas broad responses to structural and nonstructural (NS) proteins were observed after monovalent vaccination, T cell responses following tetravalent vaccination were, dramatically, focused toward the highly conserved NS proteins. Epitopes were highly conserved in a vast variety of field isolates and able to elicit multifunctional T cell responses. Detailed knowledge of the T cell response will contribute to the identification of robust correlates of protection in natural immunity and following vaccination against DENV.ImportanceThe development of effective vaccination strategies against dengue virus (DENV) infection and clinically significant disease is a task of high global public health value and significance, while also being a challenge of significant complexity. A recent efficacy trial of the most advanced dengue vaccine candidate, demonstrated only partial protection against all four DENV serotypes, despite three subsequent immunizations and detection of measurable neutralizing antibodies to each serotype in most subjects. These results challenge the hypothesis that seroconversion is the only reliable correlate of protection. Here, we show that CD8(+) T cell responses in vaccinees were readily detectable and comparable to natural dengue virus infection. Detailed knowledge of the T cell response may further contribute to the identification of robust correlates of protection in natural immunity and vaccination against DENV.

Dataset Information

Conserved epitopes with high HLA-I population coverage are targets of CD8+ T cells associated with high IFN-? responses against all dengue virus serotypes.

Publications

Conserved epitopes with high HLA-I population coverage are targets of CD8<sup>+</sup> T cells associated with high IFN-γ responses against all dengue virus serotypes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets