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High Throughput In Vitro Assessment of Latency Reversing Agents on HIV Transcription and Splicing
Published on: January 22, 2019
Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency
Hung-Chih Yang1, Sifei Xing, Liang Shan
1Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
The Journal of Clinical Investigation
|October 7, 2009
Summary
Researchers developed a novel in vitro model to find compounds that reverse HIV-1 latency. They identified 5-hydroxynaphthalene-1,4-dione (5HN), a compound that reactivates latent HIV without broad T cell activation, offering a new strategy for HIV eradication.
Area of Science:
- Virology
- Immunology
- Drug Discovery
Background:
- Highly active antiretroviral therapy (HAART) improves HIV-1 outcomes but cannot eliminate latent reservoirs.
- Latent HIV-1 in resting CD4+ T cells is a major barrier to eradication.
- Current latency-reversing strategies often cause unacceptable T cell toxicities.
Purpose of the Study:
- To develop a novel in vitro model for studying HIV-1 latency.
- To screen for compounds that can reverse HIV-1 latency without causing global T cell activation.
- To identify new therapeutic strategies for HIV-1 eradication.
Main Methods:
- Developed an in vitro model using primary CD4+ T cells transduced with Bcl-2 to mimic quiescent cells.
- Screened small-molecule libraries against this model system.
- Assessed compound-induced HIV-1 reactivation and T cell activation markers (NFAT, PKC).
Main Results:
- Identified 5-hydroxynaphthalene-1,4-dione (5HN) as a novel latency-reversing agent.
- 5HN reactivated latent HIV-1 via ROS and NF-kappaB signaling.
- 5HN did not induce global T cell activation, sparing NFAT and PKC pathways.
Conclusions:
- The novel in vitro model effectively recapitulates HIV-1 latency.
- 5HN represents a new class of latency-reversing therapeutics with a distinct mechanism.
- Targeting specific T cell pathways offers a potential strategy for safe HIV-1 eradication.
