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: 20). 05/2012; 13(3):223-8. DOI: 10.1038/ni.2236
Source: PubMed


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.


Available from: Waaqo Daddacha
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    • "Vpx interacts with the C-terminus of SAMHD1 in order to facilitate this degradation [14,39,40]. Recent reports have examined the acute kinetics of Vpx-mediated SAMHD1 degradation in myeloid cells and the enhancement of HIV-1 infection after Vpx treatment [8,41]. Further, we have reported in detail the acute effects of Vpx-mediated SAMHD1 degradation in monocyte-derived macrophages (MDMs) [42], which led to increased dNTP levels followed by enhancement of proviral DNA synthesis and transduction of MDMs. "
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    ABSTRACT: BackgroundSAMHD1 degrades deoxyribonucleotides (dNTPs), suppressing viral DNA synthesis in macrophages. Recently, viral protein X (Vpx) of HIV-2/SIVsm was shown to target SAMHD1 for proteosomal degradation and led to elevation of dNTP levels, which in turn accelerated proviral DNA synthesis of lentiviruses in macrophages.ResultsWe investigated both time-dependent and quantitative interplays between SAMHD1 level and dNTP concentrations during multiple exposures of Vpx in macrophages. The following were observed. First, SAMHD1 level was rapidly reduced by Vpx¿+¿VLP to undetectable levels by Western blot analysis. Recovery of SAMHD1 was very slow with less than 3% of the normal macrophage level detected at day 6 post Vpx treatment and only ~30% recovered at day 14. Second, dGTP, dCTP and dTTP levels peaked at day 1 post Vpx treatment, whereas dATP peaked at day 2. However, all dNTPs rapidly decreased starting at day 3, while SAMHD1 level was below the level of detection. Third, when Vpx pretreated macrophages were re-exposed to a second Vpx treatment at day 7, we observed dNTP elevation that had faster kinetics than the first Vpx¿+¿VLP treatment. Moreover, we performed a short kinetic analysis of the second Vpx treatment to find that dATP and dGTP levels peaked at 8 hours post secondary VLP treatment. dGTP peak was consistently higher than the primary, whereas peak dATP concentration was basically equivalent to the first Vpx¿+¿VLP treatment. Lastly, HIV-1 replication kinetics were faster in macrophages treated after the secondary Vpx treatments when compared to the initial single Vpx treatment.Conclusion This study reveals that a very low level of SAMHD1 sufficiently modulates the normally low dNTP levels in macrophages and proposes potential diverse mechanisms of Vpx-mediated dNTP regulation in macrophages.
    Retrovirology 08/2014; 11(1):63. DOI:10.1186/PREACCEPT-5624405321277583 · 4.19 Impact Factor
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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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    ABSTRACT: HIV-1 was recognized as the cause of AIDS in humans in 1984. Despite 30 years of intensive research, we are still unraveling the molecular details of the host-pathogen interactions that enable this virus to escape immune clearance and cause immunodeficiency. Here we explore a series of recent studies that consider how HIV-1 interacts with the cell-autonomous innate immune system as it navigates its way in and out of host cells. We discuss how these studies improve our knowledge of HIV-1 and host biology as well as increase our understanding of transmission, persistence, and immunodeficiency and the potential for therapeutic or prophylactic interventions.
    Cell Host & Microbe 07/2014; 16(1):10-18. DOI:10.1016/j.chom.2014.06.009 · 12.33 Impact Factor
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    • "The identification of the host restriction factor SAMHD1 (sterile alpha motif domain– and HD domain–containing protein 1) helped to explain the limited HIV-1 infection of DCs [17], [18]. SAMHD1 restricts infection by reducing the nucleotide pool available for reverse transcription, thereby limiting replication of the viral genome [19]. "
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    ABSTRACT: Dendritic cells (DCs) are essential in order to combat invading viruses and trigger antiviral responses. Paradoxically, in the case of HIV-1, DCs might contribute to viral pathogenesis through trans-infection, a mechanism that promotes viral capture and transmission to target cells, especially after DC maturation. In this review, we highlight recent evidence identifying sialyllactose-containing gangliosides in the viral membrane and the cellular lectin Siglec-1 as critical determinants for HIV-1 capture and storage by mature DCs and for DC-mediated trans-infection of T cells. In contrast, DC-SIGN, long considered to be the main receptor for DC capture of HIV-1, plays a minor role in mature DC-mediated HIV-1 capture and trans-infection.
    PLoS Pathogens 07/2014; 10(7):e1004146. DOI:10.1371/journal.ppat.1004146 · 7.56 Impact Factor
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