SIVSM/HIV-2 Vpx proteins promote retroviral escape from a proteasome-dependent restriction pathway present in human dendritic cells

Abstract

Background: Vpx is a non-structural protein coded by members of the SIV SM /HIV-2 lineage that is believed to have originated by duplication of the common vpr gene present in primate lentiviruses. Vpx is incorporated into virion particles and is thus present during the early steps of viral infection, where it is thought to drive nuclear import of viral nucleoprotein complexes. We have previously shown that Vpx is required for SIV MAC -derived lentiviral vectors (LVs) infection of human monocyte-derived dendritic cells (DCs). However, since the requirement for Vpx is specific for DCs and not for other non-dividing cell types, this suggests that Vpx may play a role other than nuclear import.

Tailored HIV-1 Vectors for Genetic Modification of Primary Human Dendritic Cells and Monocytes

“…A more efficient manner to remove this restriction is through the use of Vpx, a protein that counters it very efficiently by stimulating the efficiency of the process of reverse transcription (11,(17)(18)(19)(20)(21)(22)(23). Indeed, the HIV-1-Src-Vpx LVs described here efficiently degrade the restriction factor SAMHD1.…”

“…However, even in the case of LVs, efficient transduction rates of MDDCs require high viral inputs, and multiplicities of infection (MOIs) ranging from 10 to 500 have been described (3)(4)(5)(7)(8)(9)(10). Contrary to more permissive cells, MDDCs, like other human myeloid cells (monocytes and macrophages), display a strong resistance to HIV-1, a phenomenon that is particularly acute during the early phases of infection, i.e., those phases of interest for gene therapy purposes (11)(12)(13). This relative resistance can be bypassed in certain instances through the use of high doses of viral inputs (14)(15)(16), but this exposes target cells to modifications that can affect their maturation, their survival, or their functionality and that are largely due to the presence of large amounts of viral components (8)(9)(10).…”

“…We and others have previously determined that this restrictive phenotype could be relieved through the use of Vpx, a viral protein that is encoded by members of the simian immunodeficiency virus SM (SIV SM )/HIV-2 lineage and absent from HIV-1 (11,(17)(18)(19)(20)(21)(22)(23). Indeed, when provided in trans onto target MDDCs via noninfectious virion-like particles derived from SIV MAC (VLP-Vpx), Vpx increased the susceptibility of MDDCs to infection with a wide range of lentiviruses, particularly with HIV-1 (11,18,22,24).…”

“…Indeed, when provided in trans onto target MDDCs via noninfectious virion-like particles derived from SIV MAC (VLP-Vpx), Vpx increased the susceptibility of MDDCs to infection with a wide range of lentiviruses, particularly with HIV-1 (11,18,22,24). Vpx counteracts at least two restriction factors that hamper lentiviral infection in myeloid cells at the reverse transcription step: the apolipoprotein B editing catalytic polypeptide 3A (APOBEC3A) and the sterile alpha motif hydrolase domain 1 (SAMHD1) proteins (20,21,(25)(26)(27)(28)(29)(30).…”

The Susceptibility of Primate Lentiviruses to Nucleosides and Vpx during Infection of Dendritic Cells Is Regulated by CA

“…To circumvent this block, certain lentiviruses such as those belonging to the HIV-2/simian immunodeficiency virus of sooty mangabeys (SIV SM ) lineage have evolved SAMHD1-depleting abilities in Vpx (viral protein X) (10)(11)(12), a protein that is incorporated into virion particles and that is key to a successful infection (5,13,14). SAMHD1 restricts viral infection at reverse transcription, but the exact mechanism through which this is accomplished remains unclear.…”