title: cGAS-Mediated Innate Immunity Spreads Intercellularly through HIV-1 Env-Induced Membrane Fusion Sites.
abstract: Upon sensing cytoplasmic retroviral DNA in infected cells, cyclic GMP-AMP (cGAMP) synthase (cGAS) produces the cyclic dinucleotide cGAMP, which activates STING to trigger a type I interferon (IFN) response. We find that membrane fusion-inducing contact between donor cells expressing the HIV envelope (Env) and primary macrophages endogenously expressing the HIV receptor CD4 and coreceptor enable intercellular transfer of cGAMP. This cGAMP exchange results in STING-dependent antiviral IFN responses in target macrophages and protection from HIV infection. Furthermore, under conditions allowing cell-to-cell transmission of HIV-1, infected primary T cells, but not cell-free virions, deliver cGAMP to autologous macrophages through HIV-1 Env and CD4/coreceptor-mediated membrane fusion sites and induce a STING-dependent, but cGAS-independent, IFN response in target cells. Collectively, these findings identify an infection-specific mode of horizontal transfer of cGAMP between primary immune cells that may boost antiviral responses, particularly in infected tissues in which cell-to-cell transmission of virions exceeds cell-free infection.
authors.affiliation: Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.
authors.forename: Shuting
authors.initials: S
authors.lastname: Xu
authors.affiliation: Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Ducroux
authors.affiliation: Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.
authors.forename: Aparna
authors.initials: A
authors.lastname: Ponnurangam
authors.affiliation: Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Vieyres
authors.affiliation: Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.
authors.forename: Sergej
authors.initials: S
authors.lastname: Franz
authors.affiliation: Institute of Molecular Bacteriology, TWINCORE, 30625 Hanover, Germany; Department of Molecular Bacteriology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Müsken
authors.affiliation: German Center for Infection Research Cologne-Bonn, Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zillinger
authors.affiliation: Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.
authors.forename: Angelina
authors.initials: A
authors.lastname: Malassa
authors.affiliation: Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Ewald
authors.affiliation: Gene Center and Department of Biochemistry, Ludwig-Maximilians-University Munich Germany; Center for Integrated Protein Science Munich, 81377 Munich, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: German Center for Infection Research Cologne-Bonn, Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: Barchet
authors.affiliation: Institute of Molecular Bacteriology, TWINCORE, 30625 Hanover, Germany; Department of Molecular Bacteriology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Häussler
authors.affiliation: Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pietschmann
authors.affiliation: Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany. Electronic address: christine.goffinet@twincore.de.
authors.forename: Christine
authors.initials: C
authors.lastname: Goffinet
mesh_terms: D001692:Biological Transport; D002460:Cell Line; D004279:DNA, Viral / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D008561:Membrane Fusion; D008565:Membrane Proteins / Q000378:metabolism; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology*; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D004279:DNA, Viral; D007370:Interferon Type I; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; D009713:Nucleotidyltransferases; C532857:STING1 protein, human; D000099197:STING Protein; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase