PR-957, a selective immunoproteasome inhibitor, reactivates latent HIV-1 through p-TEFb activation mediated by HSF-1

The existence of latent reservoirs of Human Immunodeficiency Virus type-1 (HIV-1) is a major obstacle in eliminating the virus. Thus, an urgent need exists for effective latency reversing agents (LRAs) based on the "shock and kill" strategy. Proteasome inhibitors were recently studied as LRAs, but were considered too toxic for clinical use. Here, we demonstrated that PR-957, a selective immunoproteasome inhibitor, effectively reactivated latent HIV-1 provirus in vitro and ex vivo. Our data also suggests that PR-957 has relatively low cytotoxicity. Furthermore, it does not influence global T cell activation and decreases the expression levels of HIV-1 receptors/co-receptors. We demonstrated synergistic activation of latent HIV-1 with PR-957 and Prostratin (a protein kinase C activator) that alleviated the extent of T cell activation induced by Prostratin. In addition, PR-957 exhibited latency reversing efficacy through activating p-TEFb mediated by HSF-1 pathway. Moreover, PR-957 did not affect the activity of combination antiretroviral therapy (cART) drugs and the PR-957-reactivated virus was effectively inhibited with cART drugs. In conclusion, the immunoproteasome inhibitor PR-957 is a promising candidate LRA for future HIV-1 eradication strategies.