Integrin αvβ5 Internalizes Zika Virus during Neural Stem Cells Infection and Provides a Promising Target for Antiviral Therapy

We perform a CRISPR-Cas9 genome-wide screen in glioblastoma stem cells and identify integrin alpha v beta 5 as an internalization factor for Zika virus (ZIKV). Expression of alpha v beta 5 is correlated with ZIKV susceptibility in various cells and tropism in developing human cerebral cortex. A blocking antibody against integrin alpha v beta 5, but not alpha v beta 3, efficiently inhibits ZIKV infection. ZIKV binds to cells but fails to internalize when treated with integrin alpha v beta 5-blocking antibody. alpha v beta 5 directly binds to ZIKV virions and activates focal adhesion kinase, which is required for ZIKV infection. Finally, alpha v beta 5 blocking antibody or two inhibitors, SB273005 and cilengitide, reduces ZIKV infection and alleviates ZIKV-induced pathology in human neural stem cells and in mouse brain. Altogether, our findings identify integrin alpha v beta 5 as an internalization factor for ZIKV, providing a promising therapeutic target, as well as two drug candidates for prophylactic use or treatments for ZIKV infections.