Restricting HIV the SAMHD1 way: through nucleotide starvation
ABSTRACT HIV replication is limited by cellular restriction factors, such as APOBEC and tetherin, which themselves are counteracted by viral proteins. SAMHD1 was recently identified as a novel HIV restriction factor in myeloid cells, and was shown to be blocked by the lentiviral protein Vpx. SAMHD1 limits viral replication through an original mechanism: it hydrolyses intracellular dNTPs in non-cycling cells, thus decreasing the amount of these key substrates, which are required for viral DNA synthesis. In this Progress article, we describe how SAMHD1 regulates the pool of intracellular nucleotides to control HIV replication and the innate immune response.
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- "The deoxynucleoside triphosphate triphosphohydrolase function of SAMHD1 blocks reverse transcription of retroviral RNA by depleting the dNTP pool required for complete reverse transcription (Ayinde et al., 2012; Goldstone et al., 2011; Hollenbaugh et al., 2013; Kim et al., 2012; Lahouassa et al., 2012), an effect reversed by the addition of exogenous dN (Lahouassa et al., 2012). To explore the relationship between the triphosphohydrolase activity of SAMHD1 and apoptosis, primary monocytes were infected with HTLV-1 in the presence of increasing concentrations of exogenous dN (0–100 nM). "
ABSTRACT: Human T cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T cell leukemia and HTLV-1-associated myelopathies. In addition to T cells, HTLV-1 infects cells of the myeloid lineage, which play critical roles in the host innate response to viral infection. Investigating the monocyte depletion observed during HTLV-1 infection, we discovered that primary human monocytes infected with HTLV-1 undergo abortive infection accompanied by apoptosis dependent on SAMHD1, a host restriction factor that hydrolyzes endogenous dNTPs to below the levels required for productive reverse transcription. Reverse transcription intermediates (RTI) produced in the presence of SAMHD1 induced IRF3-mediated antiviral and apoptotic responses. Viral RTIs complexed with the DNA sensor STING to trigger formation of an IRF3-Bax complex leading to apoptosis. This study provides a mechanistic explanation for abortive HTLV-1 infection of monocytes and reports a link between SAMHD1 restriction, HTLV-1 RTI sensing by STING, and initiation of IRF3-Bax driven apoptosis.Cell host & microbe 10/2013; 14(4):422-34. · 12.19 Impact Factor
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- "Moreover, 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). Collectively, these in vitro observations define SAMHD1 as a host restriction factor for HIV-1 in cultured human cells (Ayinde et al, 2012). SAMHD1 deficiency in humans results in Aicardi-Goutières syndrome (AGS), a hereditary autoimmune encephalopathy that mimics congenital virus infection and is characterized by type I interferon (IFN) production (Crow and Livingston, 2008; Rice et al, 2009). "
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.The EMBO Journal 07/2013; 32. DOI:10.1038/emboj.2013.163 · 10.75 Impact Factor
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ABSTRACT: Viruses often deviate from their hosts in the nucleotide composition of their genomes. The RNA genome of the lentivirus family of retroviruses, including human immunodeficiency virus (HIV), contains e.g. an above average percentage of adenine (A) nucleotides, while being extremely poor in cytosine (C). Such a deviant base composition has implications for the amino acids that are encoded by the open reading frames (ORFs), both in the requirement of specific tRNA species and in the preference for amino acids encoded by e.g. A-rich codons. Nucleotide composition does obviously affect the secondary and tertiary structure of the RNA genome and its biological functions, but it does also influence phylogenetic analysis of viral genome sequences, and possibly the activity of the integrated DNA provirus. Over time, the nucleotide composition of the HIV-1 genome is exceptionally conserved, varying by less than 1% per base position per isolate within either group M, N, or O during 1983–2009. This extreme stability of the nucleotide composition may possibly be achieved by negative selection, perhaps conserving semi-stable RNA secondary structure as reverse transcription would be significantly affected for a less A-rich genome where secondary structures are expected to be more stable and thus more difficult to unfold. This review will discuss all aspects of the lentiviral genome composition, both of the RNA and of its derived double-stranded DNA genome, with a focus on HIV-1, the nucleotide composition over time, the effects of artificially humanized codons as well as contributions of immune system pressure on HIV nucleotide bias.Retrovirology 11/2012; 9(1):92. DOI:10.1186/1742-4690-9-92 · 4.77 Impact Factor