title: SAMHD1 restricts HIV-1 replication and regulates interferon production in mouse myeloid cells.
abstract: SAMHD1 restricts the replication of HIV-1 and other retroviruses in human myeloid and resting CD4(+) T cells and that is counteracted in SIV and HIV-2 by the Vpx accessory protein. The protein is a phosphohydrolase that lowers the concentration of deoxynucleoside triphosphates (dNTP), blocking reverse transcription of the viral RNA genome. Polymorphisms in the gene encoding SAMHD1 are associated with Aicardi-Goutières Syndrome, a neurological disorder characterized by increased type-I interferon production. SAMHD1 is conserved in mammals but its role in restricting virus replication and controlling interferon production in non-primate species is not well understood. We show that SAMHD1 is catalytically active and expressed at high levels in mouse spleen, lymph nodes, thymus and lung. siRNA knock-down of SAMHD1 in bone marrow-derived macrophages increased their susceptibility to HIV-1 infection. shRNA knock-down of SAMHD1 in the murine monocytic cell-line RAW264.7 increased its susceptibility to HIV-1 and murine leukemia virus and increased the levels of the dNTP pool. In addition, SAMHD1 knock-down in RAW264.7 cells induced the production of type-I interferon and several interferon-stimulated genes, modeling the situation in Aicardi-Goutières Syndrome. Our findings suggest that the role of SAMHD1 in restricting viruses is conserved in the mouse. The RAW264.7 cell-line serves as a useful tool to study the antiviral and innate immune response functions of SAMHD1.
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, New York, United States of America.
authors.forename: Ruonan
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, New York, United States of America.
authors.forename: Nicolin
authors.initials: N
authors.lastname: Bloch
authors.affiliation: Department of Pathology, University of Rochester, Rochester, New York, United States of America.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Nguyen
authors.affiliation: Center for Drug Discovery, Department of Pediatrics, Emory School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Baek
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, New York, United States of America.
authors.forename: Nathaniel R
authors.initials: NR
authors.lastname: Landau
mesh_terms: D000818:Animals; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D055785:Gene Knockdown Techniques; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D016899:Interferon-beta / Q000378:metabolism; D016086:Lentivirus; D008156:Luciferases; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D022423:Myeloid Cells / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000076106:SAM Domain and HD Domain-Containing Protein 1; D014779:Virus Replication / Q000502:physiology*
chemical_list: D017931:DNA Primers; D034741:RNA, Small Interfering; D016899:Interferon-beta; D008156:Luciferases; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins