MLN4924 is a first-in-class cancer drug that inhibits the Nedd8-activating 
enzyme (NAE). Herein, we report that MLN4924 inhibits Vpx/Vpr-induced SAMHD1 
degradation by inhibiting the neddylation of E3 ubiquitin ligase and blocks 
macaque simian immunodeficiency virus (SIVmac) replication in myeloid cells. 
SAMHD1 is required for MLN4924-mediated SIVmac inhibition. Our findings indicate 
the potential efficacy of inhibiting neddylation as an antiretroviral strategy 
and identify the readily available anticancer drug MLN4924 as a candidate agent 
for that purpose.