Proposed mechanisms of SAMHD1-mediated retroviral restriction. The diagram shows the proposed mechanisms by which SAMHD1 restricts HIV-1 infection in nondividing cells, such as myeloid cells and resting CD4⁺ T-cells. SAMHD1 possesses nuclease and dNTPase activities, which are dependent on its HD domain, but the SAM domain is required for maximal activity and nucleic acid binding. SAMHD1 functions as a dNTPase to decrease intracellular dNTP pool and thereby limits HIV-1 DNA synthesis during reverse transcription. Furthermore, SAMHD1 may directly bind and degrade retroviral RNA or viral DNA products generated in the infected cell.