In the present study, we demonstrate that RO and IVag ZIKV infection both induce robust antigen-specific Th1, TFH, plasma cell, GC B cell, IgM, and IgG responses, and that CD4+ T cells contribute to the generation of Ab responses, but not CD8+ T cell responses, and to the control of viral infection. Here, CD4 is linked to Zika virus infectious disease.