Contribution of SAM and HD domains to retroviral restriction mediated by human SAMHD1

► We studied the contribution of SAM and HD domains to the ability of SAMHD1 to block HIV-1 infection. ► The sole HD domain of SAMHD1 is sufficient to achieve potent restriction of HIV-1 and SIVmac. ► The HD domain of SAMHD1 is essential for the ability of SAMHD1 to oligomerize and bind RNA. ► Double stranded RNA inhibits the dNTPase activity of SAMHD1. ► Expression of SAMHD1 or the sole HD domain blocks infection of HIV-2, FIV, BIV, EIAV, N-MLV and B-MLV.