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.

Prior Dengue Virus Exposure Shapes T Cell Immunity to Zika Virus in Humans

“…These epitopes represent the first mapping of DENV/ZIKV cross-reactive epitopes in humans, and in most cases the cross-reactivity could be explained by identity or high similarity to sequences previously identified in one or more DENV serotypes. This finding was predicted by previous analysis conducted by the IEDB analysis resource (6) and by a recent study utilizing HLA transgenic mice (29). Nonetheless, identification of specific sequences here allows for a comprehensive assessment of whether the cross-reactivity is focused on regions that are highly conserved.…”

“…This is the first evidence in humans that previous exposure to dengue virus can influence subsequent infection with ZIKV by mounting a cross-reactive memory T cell response against ZIKV. Recent data in HLA transgenic mice demonstrated that ZIKV challenge following immunization of mice with ZIKV-specific and ZIKV/DENV cross-reactive epitopes elicited CD8 ϩ T cell responses that reduced infectious ZIKV levels, and CD8 ϩ T cell depletions confirmed that CD8 ϩ T cells mediated this protection (29). In addition, a recent paper has shown that Zika virus pathogenesis in rhesus macaques is unaffected by preexisting immunity to dengue virus (33).…”

CD8 + T Cell Immune Response in Immunocompetent Mice during Zika Virus Infection

“…Most of these studies focused on the cross talk of neutralizing antibodies between ZIKV and DENV and the structural basis for such cross-reactivity. A very recent study of ZIKV reported that DENV-specific CD8 ϩ T cell epitopes were cross-reactive to ZIKV, and this was also demonstrated in Ifnar1 Ϫ/Ϫ mice (11). In the present study, we sought to investigate whether such cross-reactivity of CD8 ϩ T cells can be observed in WT mice.…”

“…A recent publication showed that ZIKV/DENV cross-reactive peptides immunization provided protection against ZIKV infection (11). However, whether the cross talk mediated by CD8 ϩ T cells post-ZIKV infection could prevent DENV infection remains unclear.…”

“…In addition, due to the similarity of ZIKV and DENV, the cross-reactivity of the CD8 ϩ T cell immune response to ZIKV also needs to be studied. Wen et al demonstrated that DENV immune CD8 ϩ T cells were cross-reactive to ZIKV in Ifnar1 Ϫ/Ϫ mice (11). Whether the cross-reactivity can be induced in WT mouse and whether cross-reactivity of the CD8 ϩ T cell response to ZIKV can protect host against DENV infection are still unclear.…”