The study investigates the mechanism by which HIV-1 infection of macrophages is inhibited by the cellular protein SAM domain HD domain-containing protein 1 (SAMHD1). The viral accessory protein Vpx from HIV-2 and related simian immunodeficiency viruses (SIVsm/mac) counteracts this inhibition by loading SAMHD1 onto the CRL4^DCAF1^ E3 ubiquitin ligase, leading to its proteasome-dependent degradation. The authors demonstrate that Vpx specifically binds to and recruits SAMHD1 to the DCAF1-DDB1 module of the CRL4^DCAF1^ E3 ubiquitin ligase. They further show that depletion of SAMHD1 levels in macrophages enhances HIV-1 infection, and that this effect is blocked by a proteasome inhibitor. The findings reveal a novel mechanism by which Vpx enables HIV-2 and SIVsm/mac to infect macrophages, and highlight the intricate relationship between innate immune mechanisms and anti-viral defense.The study investigates the mechanism by which HIV-1 infection of macrophages is inhibited by the cellular protein SAM domain HD domain-containing protein 1 (SAMHD1). The viral accessory protein Vpx from HIV-2 and related simian immunodeficiency viruses (SIVsm/mac) counteracts this inhibition by loading SAMHD1 onto the CRL4^DCAF1^ E3 ubiquitin ligase, leading to its proteasome-dependent degradation. The authors demonstrate that Vpx specifically binds to and recruits SAMHD1 to the DCAF1-DDB1 module of the CRL4^DCAF1^ E3 ubiquitin ligase. They further show that depletion of SAMHD1 levels in macrophages enhances HIV-1 infection, and that this effect is blocked by a proteasome inhibitor. The findings reveal a novel mechanism by which Vpx enables HIV-2 and SIVsm/mac to infect macrophages, and highlight the intricate relationship between innate immune mechanisms and anti-viral defense.