Histone decrotonylation plays a distinct role in HIV latency

Area of Science:

• Epigenetics
• Virology
• Chemical Biology

Background:

• HIV latency is a major barrier to viral eradication.
• Epigenetic mechanisms, including histone modifications, play a crucial role in regulating HIV transcription and latency.
• The precise role of specific histone acylations, like crotonylation, in HIV latency is not fully understood.

Purpose of the Study:

• To investigate the role of histone deacetylase 3 (HDAC3) in HIV transcription and latency.
• To identify and characterize novel inhibitors targeting histone decrotonylation (HDCR) for the reversal of HIV latency.
• To explore the therapeutic potential of HDCR inhibition for HIV eradication.

Main Methods:

• Utilized chemical biology approaches to identify selective HDCR inhibitors (HDCRis).
• Performed genetic and chemical studies to determine the selectivity of HDCRis, including citarinostat.
• Employed molecular docking to elucidate the binding mechanism of HDCRis.
• Assessed the impact of HDCRis on histone crotonylation and HIV transcription in various cell types and preclinical models.

Main Results:

• HDAC3 inhibits HIV transcription through HDCR, independent of its deacetylase activity.
• Selective HDCRis, such as citarinostat, were identified that reverse HIV latency with minimal impact on other histone acylations.
• Citarinostat demonstrates selectivity for HDAC3 and HDAC8, binding distinct from classical HDAC inhibitors.
• HDCR inhibition robustly activates HIV transcription in diverse cellular models, including primary cells and SIV-infected nonhuman primate microglia.

Conclusions:

• HDCR is a critical epigenetic mechanism regulating HIV latency.
• Selective HDCR inhibitors represent a promising therapeutic strategy for reversing HIV latency.
• Targeting HDAC3 and HDAC8 through HDCR inhibition offers a novel approach for HIV eradication.