title: SAMHD1-dependent retroviral control and escape in mice.
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.
authors.affiliation: 1] Immunobiology Laboratory, Cancer Research UK, London Research Institute, London, UK [2] Medical Research Council Human Immunology Unit, Radcliffe Department of Medicine, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Jan
authors.initials: J
authors.lastname: Rehwinkel
authors.forename: Jonathan
authors.initials: J
authors.lastname: Maelfait
authors.forename: Anne
authors.initials: A
authors.lastname: Bridgeman
authors.forename: Rachel
authors.initials: R
authors.lastname: Rigby
authors.forename: Bruce
authors.initials: B
authors.lastname: Hayward
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Liberatore
authors.forename: Paul D
authors.initials: PD
authors.lastname: Bieniasz
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Towers
authors.forename: Luis F
authors.initials: LF
authors.lastname: Moita
authors.forename: Yanick J
authors.initials: YJ
authors.lastname: Crow
authors.forename: David T
authors.initials: DT
authors.lastname: Bonthron
authors.forename: Caetano
authors.initials: C
authors.lastname: Reis e Sousa
mesh_terms: D000818:Animals; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005822:Genetic Vectors / Q000235:genetics; D015658:HIV Infections / Q000235:genetics / Q000503:physiopathology*; D054303:HIV Reverse Transcriptase / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology / Q000502:physiology*; D007370:Interferon Type I / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D009421:Nervous System Malformations / Q000235:genetics / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism; D048348:Reverse Transcription / Q000235:genetics / Q000502:physiology*; D000076106:SAM Domain and HD Domain-Containing Protein 1
chemical_list: D007370:Interferon Type I; D009711:Nucleotides; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484281:Samhd1 protein, mouse; D020559:Monomeric GTP-Binding Proteins