Related Experiment Video
Updated: Jul 27, 2025
Humanized NOD/SCID/IL2rγnull (hu-NSG) Mouse Model for HIV Replication and Latency Studies
Published on: January 7, 2019
NSC95397 is a Novel HIV-1 Latency Reversing Agent
Randilea Nichols Doyle1, Vivian Yang1,2, Yetunde I Kayode3
1Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA.
Abstract:
The latent viral reservoir represents one of the major barriers of curing HIV-1. Focus on the "kick and kill" approach, in which virus expression is reactivated then cells producing virus are selectively depleted, has led to the discovery of many latency reversing agents (LRAs) that have furthered our understanding of the mechanisms driving HIV-1 latency and latency reversal. Thus far, individual compounds have yet to be robust enough to work as a therapy, highlighting the importance of identifying new compounds that target novel pathways and synergize with known LRAs. In this study, we identified a promising LRA, NSC95397, from a screen of ~4250 compounds. We validated that NSC95397 reactivates latent viral transcription and protein expression from cells with unique integration events and across different latency models. Co-treating cells with NSC95397 and known LRAs demonstrated that NSC95397 synergizes with different drugs under both standard normoxic and physiological hypoxic conditions. NSC95397 does not globally increase open chromatin, and bulk RNA sequencing revealed NSC95397 does not greatly increase cellular transcription. Instead, NSC95397 downregulates pathways key to metabolism, cell growth, and DNA repair - highlighting the potential of these pathways in regulating HIV-1 latency. Overall, we identified NSC95397 as a novel LRA that does not largely alter global transcription, that shows potential for synergy with known LRAs, and that may act through novel pathways not previously recognized for their ability to modulate HIV-1 latency.
Insights
Researchers discovered NSC95397, a novel latency reversing agent (LRA), that reactivates HIV-1. This compound synergizes with existing LRAs and may target new pathways to help cure HIV-1.
Area of Science:
- Virology
- Immunology
- Drug Discovery
Background:
- The latent viral reservoir is a primary obstacle to curing HIV-1.
- The "kick and kill" strategy aims to reactivate latent virus and eliminate infected cells.
- Existing latency reversing agents (LRAs) have limitations, necessitating new therapeutic compounds.
Purpose of the Study:
- To identify and characterize novel compounds that can reverse HIV-1 latency.
- To evaluate the synergistic potential of new LRAs with existing treatments.
- To elucidate the molecular mechanisms underlying the action of novel LRAs.
Main Methods:
- High-throughput screening of approximately 4250 compounds to identify potential LRAs.
- Validation of NSC95397's ability to reactivate latent viral transcription and protein expression across various models.
- Co-treatment assays with NSC95397 and known LRAs under normoxic and hypoxic conditions.
- Analysis of chromatin accessibility and bulk RNA sequencing to assess global transcriptional changes.
- Pathway analysis to identify cellular processes modulated by NSC95397.
Main Results:
- NSC95397 was identified as a potent LRA from a large compound screen.
- NSC95397 effectively reactivated latent viral transcription and protein expression in diverse cellular models.
- Significant synergy was observed when NSC95397 was combined with existing LRAs, even under hypoxic conditions.
- NSC95397 did not globally increase chromatin accessibility or cellular transcription.
- Downregulation of metabolism, cell growth, and DNA repair pathways was observed, suggesting novel mechanisms of action.
Conclusions:
- NSC95397 is a novel LRA with the potential to reactivate latent HIV-1.
- NSC95397 demonstrates significant synergy with known LRAs, offering a promising combination therapy approach.
- The compound may act through previously unrecognized pathways involving metabolic and cellular growth regulation to modulate HIV-1 latency.
More Related Videos
Related Concept Videos
01:26Size and Structure of Viral Genomes
01:10Retrovirus Life Cycles
02:33Retroviruses