HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase

Abstract

SAMHD1, an analogue of the murine interferon (IFN)-γ-induced gene Mg11 (ref. 1), has recently been identified as a human immunodeficiency virus-1 (HIV-1) restriction factor that blocks early-stage virus replication in dendritic and other myeloid cells and is the target of the lentiviral protein Vpx, which can relieve HIV-1 restriction. SAMHD1 is also associated with Aicardi-Goutières syndrome (AGS), an inflammatory encephalopathy characterized by chronic cerebrospinal fluid lymphocytosis and elevated levels of the antiviral cytokine IFN-α. The pathology associated with AGS resembles congenital viral infection, such as transplacentally acquired HIV. Here we show that human SAMHD1 is a potent dGTP-stimulated triphosphohydrolase that converts deoxynucleoside triphosphates to the constituent deoxynucleoside and inorganic triphosphate. The crystal structure of the catalytic core of SAMHD1 reveals that the protein is dimeric and indicates a molecular basis for dGTP stimulation of catalytic activity against dNTPs. We propose that SAMHD1, which is highly expressed in dendritic cells, restricts HIV-1 replication by hydrolysing the majority of cellular dNTPs, thus inhibiting reverse transcription and viral complementary DNA (cDNA) synthesis.

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

“…SAMHD1 is a dual-function enzyme with both nuclease and deoxyribonucleoside triphosphate triphosphohydrolase (dNTPase) activities (21,22). Germ-line mutations in SAMHD1 have been associated with Aicardi-Goutieres syndrome, a congenital autoimmune disease (23), and more recently SAMHD1 was shown to be an HIV-1 restriction factor operating in nondividing blood cells (24,25).…”

Effect of Ribonucleotides Embedded in a DNA Template on HIV-1 Reverse Transcription Kinetics and Fidelity

“…1 clearly demonstrates that the rNMP-mediated pausing disappears when HIV-1 RT synthesizes DNA at a fast rate with elevated dNTP concentrations. In fact, we and others recently reported that the limited dNTP pool found in macrophages is due to the expression of host restriction factor, SAMHD1, which is a dNTP triphosphohydrolase (5,45). Indeed, we also reported that HIV-2 and some SIVs encode an accessory protein, Vpx, that antagonizes the anti-viral function of SAMHD1 by proteasomal degradation.…”

Snapin promotes HIV ‐1 transmission from dendritic cells by dampening TLR 8 signaling

“…During uptake, the virus binds the C‐type lectin DC‐SIGN, which triggers a tolerogenic immune response involving downregulation of specific immune signaling molecules that may help the virus evade early detection (Hodges et al , 2007; Shan et al , 2007). Within the cytosol, HIV‐1 encounters the deoxyribose nucleoside triphosphate hydrolase SAMHD1, which limits the efficiency of HIV reverse transcription and inhibits replication (Goldstone et al , 2011; Hrecka et al , 2011; Laguette et al , 2011). This prevents detection of reverse‐transcribed viral DNA and activation of interferon responses (Gao et al , 2013; Bridgeman et al , 2015; Gentili et al , 2015).…”