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Updated: Jun 16, 2025
High Throughput In Vitro Assessment of Latency Reversing Agents on HIV Transcription and Splicing
Published on: January 22, 2019
Mechanisms and efficacy of small molecule latency-promoting agents to inhibit HIV reactivation ex vivo
Julie Janssens1,2, Peggy Kim2, Sun Jin Kim1,2
1Department of Medicine, University of California San Francisco (UCSF), San Francisco, California, USA.
Abstract:
Drugs that inhibit HIV transcription and/or reactivation of latent HIV have been proposed as a strategy to reduce HIV-associated immune activation or to achieve a functional cure, yet comparative studies are lacking. We evaluated 26 drugs, including drugs previously reported to inhibit HIV transcription (inhibitors of Tat-dependent HIV transcription, Rev, HSF-1/PTEF-b, HSP90, Jak/Stat, or SIRT1/Tat deacetylation) and other agents that were not tested before (inhibitors of PKC, NF-κB, SP-1, or histone acetyltransferase; NR2F1 agonists), elongation (inhibitors of CDK9/ PTEF-b), completion (inhibitors of PolyA-polymerase), or splicing (inhibitors of human splice factors). To investigate if those drugs would vary in their ability to affect different blocks to HIV transcription, we measured levels of initiated, elongated, midtranscribed, completed, and multiply spliced HIV RNA in PBMCs from antiretroviral therapy-suppressed individuals following ex vivo treatment with each drug and subsequent T cell activation. We identified new drugs that prevent HIV reactivation, including CDK and splicing inhibitors. While some drugs inhibited 1 or 2 steps, other drugs (CDK inhibitors, splicing inhibitors, tanespimycin, and triptolide) inhibited multiple stages of HIV transcription and blocked the production of supernatant viral RNA. These drugs and targets deserve further study in strategies aimed at reducing HIV-associated immune activation or achieving a functional cure.
Insights
Researchers evaluated 26 drugs for their ability to inhibit HIV transcription and reactivation. Several drugs, including CDK and splicing inhibitors, effectively blocked multiple stages of HIV transcription, offering new potential for HIV cure strategies.
Area of Science:
- Virology
- Immunology
- Pharmacology
Background:
- Inhibiting HIV transcription and reactivation is a strategy for reducing immune activation and achieving a functional cure.
- Comparative studies evaluating the efficacy of different drugs targeting HIV transcription are lacking.
Purpose of the Study:
- To evaluate 26 drugs for their ability to inhibit different stages of HIV transcription and reactivation.
- To identify novel drugs that can block HIV transcription and viral RNA production.
Main Methods:
- Ex vivo treatment of peripheral blood mononuclear cells (PBMCs) from antiretroviral therapy-suppressed individuals with 26 drugs.
- Measurement of initiated, elongated, midtranscribed, completed, and multiply spliced HIV RNA levels following T cell activation.
- Assessment of supernatant viral RNA production.
Main Results:
- Identified new drugs, including cyclin-dependent kinase (CDK) and splicing inhibitors, that prevent HIV reactivation.
- Some drugs inhibited one or two steps of HIV transcription, while others, like CDK inhibitors, splicing inhibitors, tanespimycin, and triptolide, inhibited multiple stages.
- Certain drugs effectively blocked the production of supernatant viral RNA.
Conclusions:
- Several novel drugs, particularly CDK and splicing inhibitors, demonstrate potent inhibition of multiple HIV transcription stages.
- These identified drugs and their targets warrant further investigation for their potential in HIV functional cure strategies and reducing HIV-associated immune activation.
