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SAMHD1-dependent retroviral control and escape in mice

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SAMHD1 is a host restriction factor for human immunodeficiency virus 1 in cultured human cells. SAMHD1 mutations cause autoimmune Aicardi-Goutières syndrome and are found in cancers including chronic lymphocytic leukemia. 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, which do not develop autoimmune disease despite displaying a type I interferon signature in spleen, macrophages and fibroblasts. Samhd1-/- cells have elevated 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. Consistent with this notion, an HIV-1 vector mutant bearing a reverse transcriptase 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.

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Correspondence to Jan Rehwinkel.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Keywords

  • Human Immunodeficiency Virus
  • Chronic Lymphocytic Leukemia
  • Null Mouse
  • Deoxynucleoside Triphosphate
  • Interferon Signature