NONO Detects the Nuclear HIV Capsid to Promote cGAS-Mediated Innate Immune Activation

• Published in: Cell Vol. 175; no. 2; pp. 488 - 501.e22
• Main Authors: Lahaye, Xavier, Gentili, Matteo, Silvin, Aymeric, Conrad, Cécile, Picard, Léa, Jouve, Mabel, Zueva, Elina, Maurin, Mathieu, Nadalin, Francesca, Knott, Gavin J., Zhao, Baoyu, Du, Fenglei, Rio, Marlène, Amiel, Jeanne, Fox, Archa H., Li, Pingwei, Etienne, Lucie, Bond, Charles S., Colleaux, Laurence, Manel, Nicolas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.10.2018; Elsevier
• Subjects: capsid; Capsid - metabolism; Capsid Proteins - immunology; Capsid Proteins - metabolism; Capsid Proteins - physiology; Cell Nucleus - metabolism; cGAS; coat proteins; dendritic cells; Dendritic Cells - immunology; DNA; DNA, Viral - genetics; DNA, Viral - immunology; DNA-Binding Proteins; enzymes; Genetics; HIV Infections - immunology; HIV-1; HIV-1 - genetics; HIV-1 - immunology; HIV-2; HIV-2 - genetics; HIV-2 - immunology; Host-Pathogen Interactions; Human genetics; Human immunodeficiency virus 1; Human immunodeficiency virus 2; Humans; immunity; Immunity, Innate - immunology; innate immune sensors; innate immunity; Life Sciences; macrophages; Macrophages - immunology; Membrane Proteins - metabolism; mutation; NONO; Nuclear Matrix-Associated Proteins - immunology; Nuclear Matrix-Associated Proteins - metabolism; Nuclear Matrix-Associated Proteins - physiology; Nucleotidyltransferases - metabolism; Nucleotidyltransferases - physiology; Octamer Transcription Factors - immunology; Octamer Transcription Factors - physiology; RNA-Binding Proteins - immunology; RNA-Binding Proteins - metabolism; RNA-Binding Proteins - physiology; Signal Transduction - immunology; STING; viruses; HIV-1; macrophages; HIV-2; dendritic cells; innate immunity; NONO; capsid; cGAS; STING; innate immune sensors
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2018.08.062

Detection of viruses by innate immune sensors induces protective antiviral immunity. The viral DNA sensor cyclic GMP-AMP synthase (cGAS) is necessary for detection of HIV by human dendritic cells and macrophages. However, synthesis of HIV DNA during infection is not sufficient for immune activation. The capsid protein, which associates with viral DNA, has a pivotal role in enabling cGAS-mediated immune activation. We now find that NONO is an essential sensor of the HIV capsid in the nucleus. NONO protein directly binds capsid with higher affinity for weakly pathogenic HIV-2 than highly pathogenic HIV-1. Upon infection, NONO is essential for cGAS activation by HIV and cGAS association with HIV DNA in the nucleus. NONO recognizes a conserved region in HIV capsid with limited tolerance for escape mutations. Detection of nuclear viral capsid by NONO to promote DNA sensing by cGAS reveals an innate strategy to achieve distinction of viruses from self in the nucleus. [Display omitted] •HIV-2, not HIV-1, activates innate immunity in macrophages and dendritic cells•NONO protein binds to the HIV-2 capsid protein with more affinity than HIV-1•NONO is an innate immune sensor of the HIV capsid in the nucleus•NONO associates with the sensor cGAS in the nucleus and enables sensing of HIV DNA The cellular factor NONO activates cGAS-mediated innate immune defenses against HIV-2 infection via viral capsid binding.