title: Restriction by SAMHD1 Limits cGAS/STING-Dependent Innate and Adaptive Immune Responses to HIV-1.
abstract: SAMHD1 is a restriction factor for HIV-1 infection. SAMHD1 mutations cause the autoinflammatory Aicardi-Goutières syndrome that is characterized by chronic type I interferon (IFN) secretion. We show that the spontaneous IFN response in SAMHD1-deficient cells and mice requires the cGAS/STING cytosolic DNA-sensing pathway. We provide genetic evidence that cell-autonomous control of lentivirus infection in myeloid cells by SAMHD1 limits virus-induced production of IFNs and the induction of co-stimulatory markers. This program of myeloid cell activation required reverse transcription, cGAS and STING, and signaling through the IFN receptor. Furthermore, SAMHD1 reduced the induction of virus-specific cytotoxic T cells in vivo. Therefore, virus restriction by SAMHD1 limits the magnitude of IFN and T cell responses. This demonstrates a competition between cell-autonomous virus control and subsequent innate and adaptive immune responses, a concept with important implications for the treatment of infection.
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine and Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Maelfait
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine and Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Bridgeman
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine and Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Adel
authors.initials: A
authors.lastname: Benlahrech
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine and Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cursi
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine and Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK. Electronic address: jan.rehwinkel@imm.ox.ac.uk.
authors.forename: Jan
authors.initials: J
authors.lastname: Rehwinkel
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D015658:HIV Infections / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D016899:Interferon-beta / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009713:Nucleotidyltransferases / Q000378:metabolism*; D000076106:SAM Domain and HD Domain-Containing Protein 1 / Q000172:deficiency / Q000378:metabolism*; D014779:Virus Replication / Q000276:immunology; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D016899:Interferon-beta; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; D000076106:SAM Domain and HD Domain-Containing Protein 1; C530855:Sting1 protein, mouse; D000099197:STING Protein; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase; C484281:Samhd1 protein, mouse