Abstract
Despite its efficiency to prevent viral multiplication, antiretroviral therapy (ART) is unable to cure patients with HIV-1. Indeed, if ART is stopped, a viral rebound is observed. This increase in blood viral load is due to the activation of HIV-1 reservoirs, among which latently-infected memory CD4+ T cells. These cells are rare (1-10 per million of quiescent T cells), appear very quickly following infection and have a long half-life (almost 4 years). To purge this long-lived reservoir the "Shock and Kill" (or kick and kill) approach was developed. This strategy relies on the use of latency reversing agents (LRAs) to induce reservoir activation. All LRAs developed until now target cellular proteins such as histone deacetylases or protein kinase C. These LRAs did not affect the reservoir size of HIV+ patients.Here we present a new LRA family that binds to and activates an HIV-1 protein. These compounds were identified by in silico screening, are not cytotoxic and affect the biological activity of their target. They were less efficient than available LRAs on HIV-1 latent cell lines. Nevertheless, when tested on latent T-cells from HIV-1 patients in ex vivo assays, the lead compound D10 at 50 nM was ~ 80% more efficient than bryostatin-1, one of the best LRA available to date.Using a chemoinformatic approach, we selected 11 analogs of D10, termed N1 to N11. Some of these analogs (N5, N8) showed a stronger effect than D10 on latent cell lines. The study of this family enabled us to elaborate a structure/ function relationship.We thus identified a new family of HIV latency reversing agents targeting a viral protein and that should therefore be more specific than LRAs that target cellular proteins.