Abstract
BackgroundSAMHD1 is a triphosphohydrolase that restricts the replication of HIV-1 and SIV in myeloid cells. In macrophages and dendritic cells, SAMHD1 restricts virus replication by diminishing the deoxynucleotide triphosphate pool to a level below that which supports lentiviral reverse transcription. HIV-2 and related SIVs encode the accessory protein Vpx to induce the proteasomal degradation of SAMHD1 following virus entry. While SAMHD1 has been shown to restrict HIV-1 and SIV, the breadth of its restriction is not known and whether other viruses have a means to counteract the restriction has not been determined.ResultsWe show that SAMHD1 restricts a wide array of divergent retroviruses, including the alpha, beta and gamma classes. Murine leukemia virus was restricted by SAMHD1 in macrophages yet removal of SAMHD1 did not alleviate the block to infection because of an additional block to viral nuclear import. Prototype foamy virus (PFV) and Human T cell leukemia virus type I (HTLV-1) were the only retroviruses tested that were not restricted by SAMHD1. PFV reverse transcribes predominantly prior to entry and thus is unaffected by the dNTP level in the target cell. It is possible that HTLV-1 has a mechanism to render the virus resistant to SAMHD1-mediated restriction.ConclusionThe results suggest that SAMHD1 has broad anti-retroviral activity against which most viruses have not found an escape.
Highlights
SAMHD1 is a triphosphohydrolase that restricts the replication of Human immunodeficiency virus (HIV)-1 and Simian immunodeficiency virus (SIV) in myeloid cells
THP-1 is a monocytic cell line that expresses endogenous SAMHD1 and that in the undifferentiated state is permissive to HIV-1 but upon differentiation with phorbol ester becomes restricted to infection [16,18]
We found that there was no significant difference in the amount of luciferase activity between monocyte-derived macrophages (MDM) pretreated with Vpx-containing and control virus-like particles (VLP) for human T cell leukemia virus type 1 (HTLV-1) (Figure 6A)
Summary
SAMHD1 is a triphosphohydrolase that restricts the replication of HIV-1 and SIV in myeloid cells. In macrophages and dendritic cells, SAMHD1 restricts virus replication by diminishing the deoxynucleotide triphosphate pool to a level below that which supports lentiviral reverse transcription. HIV-2 and related SIVs encode the accessory protein Vpx to induce the proteasomal degradation of SAMHD1 following virus entry. In HIV-2 and isolates of SIV from macaques (SIVmac), the SAMHD1-mediated restriction is counteracted by the Vpx accessory protein [3,4] whereas in viruses such as SIVagm, the restriction is counteracted by the related Vpr accessory protein. As a result of the absence of SAMHD1 the MDM of such patients support high levels of HIV-1 replication upon in vitro infection [5]
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