CD4(+) T Cells Cross-Reactive with Dengue and Zika Viruses Protect against Zika Virus Infection

The underlying mechanisms by which prior immunity to dengue virus (DENV) affords cross-protection against the related flavivirus Zika virus (ZIKV) are poorly understood. Here, we examine the ability of DENV/ZIKV-cross-reactive CD4(+) T cells to protect against versus exacerbate ZIKV infection by using a histocompatibility leukocyte antigen (HLA)-DRB1*0101 transgenic, interferon α/β receptor-deficient mouse model that supports robust DENV and ZIKV replication. By mapping the HLA-DRB1*0101-restricted T cell response, we identify DENV/ZIKV-cross-reactive CD4(+) T cell epitopes that stimulate interferon gamma (IFNγ) and/or tumor necrosis factor (TNF) production. Vaccination of naive HLA-DRB1*0101 transgenic mice with these peptides induces a CD4(+) T cell response sufficient to reduce tissue viral burden following ZIKV infection. Notably, this protective response requires IFNγ and/or TNF secretion but not anti-ZIKV immunoglobulin G (IgG) production. Thus, DENV/ZIKV-cross-reactive CD4(+) T cells producing canonical Th1 cytokines can suppress ZIKV replication in an antibody-independent manner. These results may have important implications for increasing the efficacy and safety of DENV/ZIKV vaccines and for developing pan-flavivirus vaccines.