HIV Triggers a cGAS-Dependent, Vpu- and Vpr-Regulated Type I Interferon Response in CD4+ T Cells

Several pattern-recognition receptors sense HIV-1 replication products and induce type I interferon (IFN-I) production under specific experimental conditions. However, it is thought that viral sensing and IFN induction are virtually absent in the main target cells of HIV-1 in vivo. Here, we show that activated CD4+ T cells sense HIV-1 infection through the cytosolic DNA sensor cGAS and mount a bioactive IFN-I response. Efficient induction of IFN-I by HIV-1 infection requires proviral integration and is regulated by newly expressed viral accessory proteins: Vpr potentiates, while Vpu suppresses cGAS-dependent IFN-I induction. Furthermore, Vpr also amplifies innate sensing of HIV-1 infection in Vpx-treated dendritic cells. Our results identify cGAS as mediator of an IFN-I response to HIV-1 infection in CD4+ T cells and demonstrate that this response is modulated by the viral accessory proteins Vpr and Vpu. Thus, viral innate immune evasion is incomplete in the main target cells of HIV-1. [Display omitted] •HIV infection triggers a type I interferon (IFN-I) response in primary CD4+ T cells•IFN-I induction requires integration of HIV-1 and is mediated by cGAS•HIV-1 Vpr potentiates and Vpu suppresses IFN-I induction Vermeire et al. show that the cytosolic DNA receptor cGAS senses HIV-1 infection and induces type I interferon (IFN-I) production in primary CD4+ T cells. Effective IFN-I induction requires proviral integration and expression of the HIV protein Vpr, while Vpu counteracts cGAS-mediated innate immune activation.