Diversity of small molecule HIV‐1 latency reversing agents identified in low‐ and high‐throughput small molecule screens

Abstract

The latency phenomenon produced by human immunodeficiency virus (HIV-1) prevents viral clearance by current therapies, and consequently development of a cure for HIV-1 disease represents a formidable challenge. Research over the past decade has resulted in identification of small molecules that are capable of exposing HIV-1 latent reservoirs, by reactivation of viral transcription, which is intended to render these infected cells sensitive to elimination by immune defense recognition or apoptosis. Molecules with this capability, known as latency-reversing agents (LRAs) could lead to realization of proposed HIV-1 cure strategies collectively termed "shock and kill," which are intended to eliminate the latently infected population by forced reactivation of virus replication in combination with additional interventions that enhance killing by the immune system or virus-mediated apoptosis. Here, we review efforts to discover novel LRAs via low-and high-throughput small molecule screens, and summarize characteristics and biochemical properties of chemical structures with this activity.We expect this analysis will provide insight toward further research into optimized designs for new classes of more potent LRAs.---

Block-And-Lock: New Horizons for a Cure for HIV-1

“…This strategy is known as shock-and-kill ( Figure 2 ) [ 83 , 84 , 85 ]. As of today, more than 300 molecules have been evaluated in vitro to reactivate latent HIV-1, including epigenetic, chromatin, signaling, and transcription modulators [ 86 , 87 ]. The chromatin-modifying agents, HDAC inhibitors (e.g., Vorinostat, Romidepsin and Panobinostat), are the most characterized class of LRAs explored in shock-and-kill approaches [ 86 ].…”

“…As of today, more than 300 molecules have been evaluated in vitro to reactivate latent HIV-1, including epigenetic, chromatin, signaling, and transcription modulators [ 86 , 87 ]. The chromatin-modifying agents, HDAC inhibitors (e.g., Vorinostat, Romidepsin and Panobinostat), are the most characterized class of LRAs explored in shock-and-kill approaches [ 86 ]. Three clinical trials using vorinostat clearly demonstrated an increase in HIV-1 RNA in resting CD4 + T cells; however, this was insufficient for robust protein production and did not have a meaningful impact on the size of the HIV-1 reservoir [ 88 , 89 , 90 ].…”

The African natural product knipholone anthrone and its analogue anthralin (dithranol) enhance HIV-1 latency reversal

“…To date, numerous LRAs have been reported to act through two major cellular pathways: PKC activation and HDAC inhibition (10,11). To determine whether KA and anthralin function as PKC activators, we asked if their activities in live J-Lat 9.2 cells were antagonized by the pan-PKC inhibitor GÖ-6983 (27).…”

“…Numerous LRAs have been described representing different functional classes. The majority represents protein kinase C (PKC) activators and histone deacetylase (HDAC) inhibitors, although agents that act by other mechanisms such as BET bromodomain and DNA methyltransferase inhibition are also intensively studied (10,11). However, LRAs tested to date in humans have shown limited clinical success due to extensive toxicity, poor efficacy, inconsistent viral reactivation, and/or insufficient engagement of cellular "kill" mechanisms (10,12).…”

Identification of Celastrol as a novel HIV-1 Latency Reversal Agent by an Image-Based Screen

“…The "kill" involves the immune system's ability to recognize and clear cells that express viral antigens. A number of small molecules have been identified that function as latency reversal agents (LRAs) in CD4 + T cell lines and patient cells ex vivo [reviewed in [10][11][12]]. One class of LRAs are PKC agonists which function through activation of NF-B and the subsequent stimulation of RNAP II transcription via the NF-κB sites in the viral long terminal repeat (LTR) sequences.…”