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Top Down Computational Approach: A Vaccine Development Step to Find Novel Superantigenic HLA Binding Epitopes from Dengue Virus Proteome.

ABSTRACT: Dengue virus (DENV) is a major mosquito vector based human pathogenic flavivirus which is causing major threat worldwide, yet the availability of therapeutic treatment and several vaccines, still called for advance treatment and vaccine development. The present top down computational approach is a vaccine development step to find novel super antigenic HLA binding epitopes from DENV proteome. The approach used sequence based screening to find complete conserve and high population coverage, common epitopes among all DENV serotype. Propred and Immune Epitope Data Base were used for sequence based screening with recommended parameters. Among top 29 identified epitopes, five structural protein epitopes viz. ³³LQGRGPLKL⁴¹, ²⁴⁹VVVLGSQEG²⁵⁷, ¹⁷²LVGIVTLYL¹⁸⁰, ¹⁴⁶MKILIGVVI¹⁵⁴, ⁷²YIIVGVEPG⁸⁰ and one nonstructural protein epitope ¹⁸LKNDIPMTG²⁶ were showed high conserve nature and high population coverage from complete DENV proteome. Further structure based study involving docking and molecular dynamic simulation to confirm stable behavior of HLA allele-peptide complex to give potent cell mediated immune response. Docking of epitope ⁷²YIIVGVEPG⁸⁰-DRB1 0401 allele and epitope ³³LQGRGPLKL⁴¹-B*5101 allele complexes showed the best binding energy of - 7.71 and - 7.20 kcal/mol, respectively and stable binding pattern over the time window during molecular dynamic simulation. This computational approach resulted novel epitopes which can be used in the design and development of short epitope based vaccines as well as diagnosis tools for dengue infection.

SUBMITTER: Sharma P

PROVIDER: S-EPMC7921607 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Top Down Computational Approach: A Vaccine Development Step to Find Novel Superantigenic HLA Binding Epitopes from Dengue Virus Proteome.

Sharma Priti P Sharma Pawan P Sheeba Kumar Ajay A

International journal of peptide research and therapeutics 20210302 2

Dengue virus (DENV) is a major mosquito vector based human pathogenic flavivirus which is causing major threat worldwide, yet the availability of therapeutic treatment and several vaccines, still called for advance treatment and vaccine development. The present top down computational approach is a vaccine development step to find novel super antigenic HLA binding epitopes from DENV proteome. The approach used sequence based screening to find complete conserve and high population coverage, common ...[more]

PMID: 33679273

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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.

Dataset Information

Top Down Computational Approach: A Vaccine Development Step to Find Novel Superantigenic HLA Binding Epitopes from Dengue Virus Proteome.

Publications

Top Down Computational Approach: A Vaccine Development Step to Find Novel Superantigenic HLA Binding Epitopes from Dengue Virus Proteome.

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