High-throughput screening to identify novel STAT-5 pathway activators for potential HIV latency reversal therapeutics

Authors

• E Vanlal
• M Xu
• CZ Chen
• A Bosque

Abstract

Human immunodeficiency virus (HIV) has caused more than 35 million deaths worldwide. Management of the disease requires the daily administration of a combination of antiretroviral (ART) drugs for the life of the infected individual. However, HIV reservoirs, such as CD4+ T cells, where HIV lay transcriptionally dormant, pose a significant challenge in achieving complete eradication of HIV. The 'Shock and Kill' strategy aims to reactivate these latent HIV reservoirs using latency-reversing agents (LRAs), allowing their elimination by the immune system. Previous studies identified 3-Hydroxy-1,2.3-benzotriazin-4(SH)-one (HODHBt) as an LRA through activation of the STAT-5 pathway. Besides its ability to reactivate latent HIV, we have recently demonstrated that this compound enhances the immune effector function of natural killer (NK) and HIV-specific CD8T cells. However, HODHBt is not a drug-like molecule. To identify other small molecule STAT-5 activators, we have adapted an assay using HEK293 stably expressing IL-2 receptor and a STAT5 reporter. This assay was successfully optimized and miniaturized to 1536-well plate format and used to screen a collection of 20k small molecules, which includes approved and investigational drugs, and compounds of diverse structures with unknown activities.

Scientific Focus Area: Molecular Pharmacology

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