Our work extends published observations on SAMHD1 nuclear localization to a natural cell type for HIV-1 infection, identifies KPNA2/KPNB1 as cellular factors important for SAMHD1 nuclear import, and indicates that components of the nuclear proteasomal degradation machinery are required for Vpx induced SAMHD1 degradation. Here, KPNA2 is linked to HIV-1 infection.