title: Identification of Zika virus epitopes reveals immunodominant and protective roles for dengue virus cross-reactive CD8+T cells.
abstract: CD8+T cells play an important role in controlling Flavivirus infection, including Zika virus (ZIKV). Here, we have identified 25 HLA-B*0702-restricted epitopes and 1 HLA-A*0101-restricted epitope using interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) and intracellular cytokine staining (ICS) in ZIKV-infected IFN-α/β receptor-deficient HLA transgenic mice. The cross-reactivity of ZIKV epitopes to dengue virus (DENV) was tested using IFN-γ-ELISPOT and IFN-γ-ICS on CD8+T cells from DENV-infected mice, and five cross-reactive HLA-B*0702-binding peptides were identified by both assays. ZIKV/DENV cross-reactive CD8+T cells in DENV-immune mice expanded post ZIKV challenge and dominated in the subsequent CD8+T cell response. ZIKV challenge following immunization of mice with ZIKV-specific and ZIKV/DENV cross-reactive epitopes elicited CD8+T cell responses that reduced infectious ZIKV levels, and CD8+T cell depletions confirmed that CD8+T cells mediated this protection. These results identify ZIKV-specific and ZIKV/DENV cross-reactive epitopes and demonstrate both an altered immunodominance pattern in the DENV-immune setting relative to naive, as well as a protective role for epitope-specific CD8+T cells against ZIKV. These results have important implications for ZIKV vaccine development and provide a mouse model for evaluating anti-ZIKV CD8+T cell responses of human relevance.
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy &Immunology, La Jolla, California 92037, USA.|Institute of Arboviruses, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
authors.forename: Jinsheng
authors.initials: J
authors.lastname: Wen
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy &Immunology, La Jolla, California 92037, USA.
authors.forename: William Weihao
authors.initials: WW
authors.lastname: Tang
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy &Immunology, La Jolla, California 92037, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Sheets
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy &Immunology, La Jolla, California 92037, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Ellison
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy &Immunology, La Jolla, California 92037, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy &Immunology, La Jolla, California 92037, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kim
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy &Immunology, La Jolla, California 92037, USA.
authors.forename: Sujan
authors.initials: S
authors.lastname: Shresta
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003429:Cross Reactions; D003716:Dengue Virus / Q000276:immunology*; D058501:Enzyme-Linked Immunospot Assay; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015234:HLA-A Antigens / Q000378:metabolism; D015235:HLA-B Antigens / Q000378:metabolism; D007371:Interferon-gamma / Q000032:analysis; D051379:Mice; D013194:Staining and Labeling; D000071244:Zika Virus / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D007371:Interferon-gamma