The histone methyltransferase SETD2 regulates HIV expression and latency

Area of Science:

• Epigenetics and Viral Latency
• Molecular Virology
• Chromatin Biology

Background:

• Understanding HIV expression and latency is crucial for developing an effective HIV cure.
• The SETD2 histone methyltransferase and its product, H3K36 trimethylation (H3K36me3), are implicated in gene regulation.
• The precise role of SETD2 and H3K36me3 in the HIV life cycle remains largely unexplored.

Purpose of the Study:

• To investigate the role of SETD2 and H3K36me3 in regulating HIV integration, expression, and latency.
• To determine the impact of SETD2 inhibition on viral gene expression and the establishment of HIV latency.
• To explore potential therapeutic strategies targeting SETD2 for HIV eradication.

Main Methods:

• Utilized a potent and selective SETD2 inhibitor (EPZ-719) to prevent H3K36me3 deposition in HIV-infected cells.
• Employed CRISPR/Cas9-mediated knockout of SETD2 in primary CD4 T cells.
• Performed transcriptomic profiling and analyzed HIV integration site distribution.
• Assessed viral RNA splicing and the responsiveness of latent HIV to HDAC inhibitors.

Main Results:

• SETD2 inhibition reduced post-integration viral gene expression and accelerated the emergence of latently infected cells.
• SETD2 depletion shifted HIV integration sites from actively transcribed genes to quiescent and polycomb-repressed chromatin regions.
• SETD2 inhibition did not affect HIV RNA levels but modestly reduced viral RNA splicing, suggesting post-transcriptional regulation.
• EPZ-719 exposure enhanced the reactivation of latent HIV by the HDAC inhibitor vorinostat.

Conclusions:

• SETD2 and H3K36me3 are novel regulators of HIV integration, expression, and latency.
• Targeting SETD2 influences HIV chromatin integration and epigenetic state, impacting viral persistence.
• These findings suggest that epigenetic modifiers like SETD2 could be valuable targets for HIV cure strategies, particularly in combination therapies.