Proposed model for HIV restrictions in primary resting CD4 T cells and counteraction by SIV Vpx variants. (A) Both SAMHD1 (RT block 1) and an unknown factor (RT block 2) are able to restrict HIV at the level of reverse transcription. Downstream, an unknown factor limits nuclear import of the preintegration complex (NI block 1). (B) SIVmac239 Vpx WT targets SAMHD1 for degradation to overcome RT block 1. In the presence of SAMHD1 and RT block 2, SAMHD1 is the preferred target of SIVmac239 Vpx WT, but in the absence of SAMHD1, RT block 2 is targeted. SAMHD1 degradation-deficient mutants of SIVmac239 Vpx target RT block 2 similarly to SIVmnd-2 and SIVrcm Vpx through a mechanism that likely involves proteasomal degradation. (C) SIVmnd-2 and SIVrcm Vpx are unable to target SAMHD1 for degradation but apparently overcome the major restriction at the level of reverse transcription by targeting RT block 2. Despite highly efficient reverse transcription, levels of 2-LTR circles are similar to those observed with SIVmac239 Vpx, indicating that also under these conditions, nuclear import is restricted by NI block 1.