In the present study, CD4+ T cells play a dominant role in promoting humoral immunity to ZIKV after infection via both systemic and genital mucosal routes, and CD4+ T cells, but not CD8+ T cells, contribute to local control of ZIKV infection in the vagina and protect against lethal disease following IVag ZIKV challenge. This evidence concerns the gene CD4 and Zika virus infectious disease.