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Updated: Jun 6, 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, CA 90095, USA.
Abstract:
The latent viral reservoir represents one of the major barriers to curing HIV-1. Focus on the "kick and kill" (also called "shock and kill") approach, in which virus expression is reactivated, and 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 that 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, shows potential for synergy with known LRAs, and may act through novel pathways not previously recognized for their ability to modulate HIV-1 latency.
Insights
Researchers discovered NSC95397, a novel compound that reactivates latent HIV-1. This latency-reversing agent (LRA) shows potential for synergy with existing therapies, offering new hope for HIV-1 cure strategies.
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 involves reactivating latent virus and eliminating infected cells.
- Latency-reversing agents (LRAs) are crucial for understanding and targeting HIV-1 latency.
Purpose of the Study:
- To identify novel compounds that can reverse HIV-1 latency.
- To investigate the synergistic potential of new LRAs with existing treatments.
- To elucidate the mechanisms by which novel LRAs modulate HIV-1 latency.
Main Methods:
- Screening of approximately 4250 compounds to identify potential LRAs.
- Validation of NSC95397's ability to reactivate latent viral transcription and protein expression across diverse latency models.
- Co-treatment experiments with NSC95397 and known LRAs under normoxic and hypoxic conditions.
- Analysis of chromatin accessibility and global transcription via bulk RNA sequencing.
Main Results:
- NSC95397 was identified as a promising LRA that reactivates latent HIV-1.
- NSC95397 demonstrated synergistic effects when combined with existing LRAs under both normoxic and hypoxic conditions.
- NSC95397 does not globally increase chromatin accessibility or cellular transcription.
- NSC95397 downregulates key metabolic and cell growth pathways, suggesting novel mechanisms of action.
Conclusions:
- NSC95397 is a novel LRA with potential for HIV-1 cure strategies.
- The compound exhibits synergy with known LRAs, enhancing the "kick and kill" approach.
- NSC95397 may act through previously unrecognized pathways involved in regulating HIV-1 latency, particularly those related to metabolism and cell growth.
