Epigenetic Compound Screening Uncovers Small Molecules for Reactivation of Latent HIV-1

During infection with the human immunodeficiency virus type 1 (HIV-1), latent reservoirs are established that circumvent full eradication of the virus by antiretroviral therapy (ART) and are the source for viral rebound after cessation of therapy. As these reservoirs are phenotypically indistinguishable from infected cells, current strategies aim to reactivate these reservoirs, followed by pharmaceutical and immunological destruction of the cells. Here, we employed a simple and convenient cell-based reporter system, which enables sample handling under biosafety level (BSL)-1 conditions, to screen for compounds that were able to reactivate latent HIV-1. The assay showed a high dynamic signal range and reproducibility with an average Z-factor of 0.77, classifying the system as robust. The assay was used for high-throughput screening (HTS) of an epigenetic compound library in combination with titration and cell-toxicity studies and revealed several potential new latency-reversing agents (LRAs). Further validation in well-known latency model systems verified earlier studies and identified two novel compounds with very high reactivation efficiencies and low toxicity. Both drugs, namely, N-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide (HPOB) and 2',3'-difluoro-[1,1'-biphenyl]-4-carboxylic acid, 2-butylhydrazide (SR-4370), showed comparable performances to other already known LRAs, did not activate CD4+ T cells, and did not cause changes in the composition of peripheral blood mononuclear cells (PBMCs), as shown by flow cytometry analyses. Both compounds may represent effective new treatment possibilities for reversal of latency in HIV-1-infected individuals.

 

Comments:

This excerpt discusses a study focused on identifying compounds that can reactivate latent reservoirs of HIV-1, which are responsible for viral rebound after stopping antiretroviral therapy (ART). The goal is to reactivate these latent reservoirs and subsequently eliminate the infected cells. The study employs a cell-based reporter system to screen for compounds that can reactivate latent HIV-1 while ensuring safety under biosafety level (BSL)-1 conditions.

Key points:

1. **Latent Reservoirs of HIV-1**: During HIV-1 infection, latent reservoirs are established, making it difficult to completely eradicate the virus using antiretroviral therapy. These reservoirs remain hidden and contribute to viral rebound upon therapy cessation.

2. **Cell-Based Reporter System**: A simple and convenient assay is used, allowing for safe handling of samples under BSL-1 conditions. This system screens compounds that can reactivate latent HIV-1.

3. **High-Throughput Screening (HTS)**: An epigenetic compound library is screened using this assay, followed by titration studies and assessments of cell toxicity. Several potential new latency-reversing agents (LRAs) are identified.

4. **Validation and Identification of Novel Compounds**: Further validation using established latency model systems confirms earlier findings and identifies two new compounds—HPOB and SR-4370—with high reactivation efficiencies and low toxicity.

5. **Comparison to Known LRAs**: Both HPOB and SR-4370 demonstrate performances comparable to other known LRAs. Importantly, they do not activate CD4+ T cells or cause changes in the composition of peripheral blood mononuclear cells (PBMCs), as observed through flow cytometry analyses.

6. **Potential Treatment Possibilities**: Both compounds represent promising new treatment options for reversing HIV-1 latency in infected individuals.

This study highlights the importance of identifying compounds capable of reactivating latent HIV-1 reservoirs while emphasizing the safety, efficiency, and potential therapeutic impact of the newly discovered compounds, HPOB and SR-4370.

Related Products

Cat.No.	Product Name	Information
S2132	SR-4370	SR-4370 is a potent and selective inhibitor of class I HDACs with IC50 of 0.13 µM, 0.58 µM, 0.006 µM, 2.3 µM, 3.7 µM for HDAC 1, HDAC 2, HDAC 3, HDAC 8, HDAC 6, respectively.SR-4370 suppresses AR signaling and in vivo prostate tumor growth.

Related Targets

HDAC