Modulation of cell-intrinsic innate immunity to improve “shock-and-kill” strategies of HIV-1 cure

• Applicant: Professorin Dr. Christine Goffinet
• Subject Area: Virology
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 318285744

The overall goal of this follow-up research proposal is to define the contribution of base-line, cell-intrinsic innate immunity to HIV-1 latency establishment and reversal. The overarching hypothesis is that current “shock-and-kill” strategies suffer from the presence of cell-intrinsic innate immunity and/or its concurrent activation by the “shock” element, which impairs full-blown HIV-1 reactivation due to the contribution of tonic expression levels of PRRs, including cGAS, and cellular restriction factors with post-integrational antiviral activity. Based on our recent findings and our previous expertise on cell-intrinsic immunity in T-cells in the context of HIV-1 infection, we will establish the cGAS-dependent gene expression profile in HIV-1-relevant target cells and define the expression profiles of key pattern recognition receptors and antiviral interferon-stimulated genes upon treatment with individual latency-reversing agents and combinations thereof. Using established model cell lines and cells from aviremic HIV-1 patients, we will investigate to which degree cGAS contributes to HIV-1 latency establishment and analyze the impact of cGAS on pharmacological reactivation of HIV-1. Finally, we will probe inhibition of cGAS activity and signaling as a strategy to improve LRA-mediated HIV-1 reactivation in T-cells. This work has the potential to widen our understanding on the interplay of HIV-1 latency and cell-intrinsic innate immunity, and to improve currently inefficient “shock-and-kill” approaches of HIV-1 cure.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1923: Innate Sensing and Restriction of Retroviruses