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

Xavier Lahaye, Matteo Gentili, Aymeric Silvin, Cécile Conrad, Léa Picard, Mabel Jouve, Elina Zueva, Mathieu Maurin, Francesca Nadalin, Gavin J. Knott, Baoyu Zhao, Fenglei Du, Marlène Rio, Jeanne Amiel, Archa H. Fox, Pingwei Li, Lucie Etienne, Charles S. Bond, Laurence Colleaux, Nicolas Manel

Research output: Contribution to journalArticlepeer-review

144 Citations (Scopus)


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. The cellular factor NONO activates cGAS-mediated innate immune defenses against HIV-2 infection via viral capsid binding.

Original languageEnglish
Pages (from-to)488-501.e22
Issue number2
Publication statusPublished - 4 Oct 2018


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