Abstract
SAMHD1 is a host restriction factor for human immunodeficiency virus 1 (HIV-1) in cultured human cells. SAMHD1 mutations cause autoimmune Aicardi-Goutières syndrome and are found in cancers including chronic lymphocytic leukaemia. SAMHD1 is a triphosphohydrolase that depletes the cellular pool of deoxynucleoside triphosphates, thereby preventing reverse transcription of retroviral genomes. However, in vivo evidence for SAMHD1's antiviral activity has been lacking. We generated Samhd1 null mice that do not develop autoimmune disease despite displaying a type I interferon signature in spleen, macrophages and fibroblasts. Samhd1(-/-) cells have elevated deoxynucleoside triphosphate (dNTP) levels but, surprisingly, SAMHD1 deficiency did not lead to increased infection with VSV-G-pseudotyped HIV-1 vectors. The lack of restriction is likely attributable to the fact that dNTP concentrations in SAMHD1-sufficient mouse cells are higher than the KM of HIV-1 reverse transcriptase (RT). Consistent with this notion, an HIV-1 vector mutant bearing an RT with lower affinity for dNTPs was sensitive to SAMHD1-dependent restriction in cultured cells and in mice. This shows that SAMHD1 can restrict lentiviruses in vivo and that nucleotide starvation is an evolutionarily conserved antiviral mechanism.
Highlights
Human dendritic cells (DCs) and other myeloid cells in culture are largely refractory to infection with human immunodeficiency virus 1 (HIV-1) (Manel et al, 2010)
Unlike serum samples from Aicardi-Goutieres syndrome (AGS) patients (Goutieres et al, 1998), sera from SAMHD1-deficient and littermate control mice did not contain detectable IFN as measured by a sensitive bioassay based on induction of the IFN-stimulated gene (ISG), IFIT1 (Figure 1B)
Transcript levels of the ISG IFIT2 or of the pro-inflammatory cytokine TNFa were not increased in lung, kidney and heart from Samhd1 À / À mice when compared to tissues from wild-type mice (Figure 1C)
Summary
Human dendritic cells (DCs) and other myeloid cells in culture are largely refractory to infection with human immunodeficiency virus 1 (HIV-1) (Manel et al, 2010). Consistent with that model, SAMHD1 depletion by Vpx delivery or RNA interference renders many human myeloid cells and resting T cells more permissive to HIV-1 infection (Berger et al, 2011; Hrecka et al, 2011; Laguette et al, 2011; Baldauf et al, 2012; Descours et al, 2012; Kim et al, 2012; Lahouassa et al, 2012). Monocytes and resting T cells from SAMHD1-deficient individuals more efficiently support HIV-1 replication (Berger et al, 2011; Baldauf et al, 2012; Descours et al, 2012) These in vitro observations define SAMHD1 as a host restriction factor for HIV-1 in cultured human cells (Ayinde et al, 2012)
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