Lahouassa H, Daddacha W, Hofmann H et al.SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat Immunol 13:223-228

Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France.
Nature Immunology (Impact Factor: 24.97). 05/2012; 13(3):223-8. DOI: 10.1038/ni.2236
Source: PubMed

ABSTRACT SAMHD1 restricts the infection of dendritic and other myeloid cells by human immunodeficiency virus type 1 (HIV-1), but in lentiviruses of the simian immunodeficiency virus of sooty mangabey (SIVsm)-HIV-2 lineage, SAMHD1 is counteracted by the virion-packaged accessory protein Vpx. Here we found that SAMHD1 restricted infection by hydrolyzing intracellular deoxynucleoside triphosphates (dNTPs), lowering their concentrations to below those required for the synthesis of the viral DNA by reverse transcriptase (RT). SAMHD1-mediated restriction was alleviated by the addition of exogenous deoxynucleosides. An HIV-1 with a mutant RT with low affinity for dNTPs was particularly sensitive to SAMHD1-mediated restriction. Vpx prevented the SAMHD1-mediated decrease in dNTP concentration and induced the degradation of human and rhesus macaque SAMHD1 but had no effect on mouse SAMHD1. Nucleotide-pool depletion could be a general mechanism for protecting cells from infectious agents that replicate through a DNA intermediate.

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Available from: Waaqo Daddacha, Aug 23, 2015
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    • "SAMHD1 is a restriction factor expressed widely in myeloid cell lineages and resting T cells (Baldauf et al., 2012; Laguette et al., 2011). Restriction by SAMHD1 is mediated by reduction of nucleotide pools to levels where reverse transcription cannot proceed, although the restriction mechanism may be more complex than this simple model (Goldstone et al., 2011; Lahouassa et al., 2012). SAMHD1 appears to be particularly important for protecting dendritic cells from HIV-1 infection (Manel et al., 2010). "
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    • "reverse transcriptase (RT) has a relatively high binding affinity for dNTPs, as compared to MLV (Weiss et al., 2004), which facilitates replication in cells with reduced dNTP content such as MDMs (Diamond et al., 2004). In line with this, HIV-1 RT mutant V148I, which has reduced dNTP binding affinity (Diamond et al., 2003, 2004), decreases HIV-1's ability to infect MDMs (Diamond et al., 2004; Lahouassa et al., 2012). Whether the RTs of HIV-2/SIVsmm have lower dNTP binding affinities than HIV-1 RT is currently unknown, but this could contribute to their dependence upon vpx. "
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    • "In contrast, LINE-1 inhibition by SAMHD1 is observed in dividing cells. SAMHD1's dNTPase activity depends on residues H167, H206, D207, and D311 within the HD domain (Aravind and Koonin, 1998; Goldstone et al., 2011; Powell et al., 2011) and is crucial for retroviral inhibition because mutations at H206/D207 compromise both enzymatic activity and antiviral potency (Kim et al., 2012; Laguette et al., 2011; Lahouassa et al., 2012). However, in our study, the D311A mutation, which depletes the hydrolase activity of SAMHD1 (Goldstone et al., 2011), still functions as a LINE-1 inhibitor. "
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