Finding a CURE for 37 Million individuals living with HIV/AIDS is one of the great global health challenges of the 21st century. The major obstacle to HIV eradication in patients under combination Anti-Retroviral therapy (cART) is the persistence of latent HIV cellular reservoirs, where the integrated viral genome is transcriptionally silenced but replication competent, and can escape both cART and immune response. Current strategies towards an HIV CURE aim at purging persisting latent reservoirs by forcing viral gene expression using epigenetic-modifying agents, including Histone Deacetylase inhibitors (HDACi) while maintaining patients on suppressive cART. However, in clinical trials, HDACi including SAHA, when used as single agents, have limited impact in inducing full HIV replication cycle or reducing latent reservoirs. Theses studies highlight that additional layers of control for HIV gene silencing limit the impact of current strategies. These blocks, which remain to be uncovered, need to be collectively unlocks if we want to eradicate these latent reservoirs. Here, we propose a new perspective to the multifaceted problem of HIV latency and persistence. Indeed, we have identified the SUMOylation system as a novel potential target for intervention, as we revealed that SUMO modifications target the silenced promoter in latently infected cells. SUMOylation is a reversible covalent post-translational modification regulating chromatin-associated processes including epigenetic gene silencing. In this proposal, we aim to target SUMO-associated chromatin events associated with the maintenance of HIV latency with specific SUMO inhibitors (SUMOi) and develop new SUMOi-based combination of LRAs. For this purpose, we will conduct pre-clinical studies using bona fine HIV+ patient blood samples, where reside the latent reservoirs, to evaluate the capacity of SUMOi-based LRAs to reactivate HIV from latency. These pre-clinical studies will constitute proof of concepts and the first critical step towards the development of innovative latency-reversing strategies as part of HIV CURE approach
