BRD9 functions as an HIV-1 latency regulatory factor.

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• HIV-1 cure is hindered by latent viral reservoirs.
• The "Shock & Kill" strategy aims to reactivate and eliminate these reservoirs.
• Current latency reversal agents (LRAs) show limited efficacy in fully reactivating latent HIV-1.

Purpose of the Study:

• To identify novel regulators of HIV-1 latency.
• To investigate the role of bromodomain-containing protein 9 (BRD9) in HIV-1 latency.

Main Methods:

• Inhibition, gene depletion, and protein degradation of BRD9.
• Assays in T cell lines, human resting memory CD4+ T cells, and PBMCs from people living with HIV-1 (PWH) on ART.
• CUT&RUN DNA sequencing, transcriptomics, and pharmacological analysis.

Main Results:

• BRD9 inhibition consistently reactivated HIV-1 latency across different cell types.
• BRD9 inhibition synergized with BRD4 inhibition to enhance HIV-1 production.
• BRD9 was found to bind the HIV-1 LTR promoter, competing with HIV-1 Tat.
• Downstream host targets ATAD2 and MTHFD2 were identified as BRD9 modulators of HIV-1 latency.

Conclusions:

• BRD9 is a novel regulator of HIV-1 latency.
• Targeting BRD9 represents a promising strategy for HIV-1 cure research.
• Understanding BRD9's mechanism provides insights into host-pathogen interactions in HIV-1 latency.