SAMHD1: a new insight into HIV-1 restriction in myeloid cells

Abstract

Human myeloid-lineage cells are refractory to HIV-1 infection. The Vpx proteins from HIV-2 and sooty mangabey SIV render these cells permissive to HIV-1 infection through proteasomal degradation of a putative restriction factor. Two recent studies discovered the cellular protein SAMHD1 to be this restriction factor, demonstrating that Vpx induces proteasomal degradation of SAMHD1 and enhances HIV-1 infection in myeloid-lineage cells. SAMHD1 functions as a myeloid-cell-specific HIV-1 restriction factor by inhibiting viral DNA synthesis. Here we discuss the implications of these findings in delineating the mechanisms of HIV-1 restriction in myeloid-lineage cells and the potential role of Vpx in lentiviral pathogenesis.

Figure 1

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.