Vpx interacts with the E3 ubiquitin ligase complex to target the restriction factor SAMHD1 for proteasomal degradation. Human myeloid-lineage cells that are non-permissive to HIV-1 infection express high levels of SAMHD1, which appears to act early in infection at the reverse transcription step. HIV-1 has not evolved a viral antagonist to counter this restriction; however, SIVsm/SIVmac and HIV-2 express Vpx to circumvent this restriction. Vpx targets SAMHD1 using the host cell E3 ubiquitin ligase complex, in which Vpx interacts with the DCAF1 subunit of the CUL4A/DDB1 ubiquitin ligase to degrade SAMHD1 via the proteasome. This allows HIV-1 reverse transcription to occur and viral replication to complete.