The RNA-binding protein RBM39 scaffolds an m⁶A-dependent RNA decay complex that destabilizes Tat transcripts and...

Area of Science:

• Virology
• Molecular Biology
• Epigenetics

Background:

• Latent HIV-1 reservoirs are a major obstacle to curing AIDS.
• Current latency-reversing agents (LRAs) have limited clinical effectiveness.
• The role of RNA modifications like N⁶-methyladenosine (m⁶A) in HIV-1 latency is not well understood.

Purpose of the Study:

• To identify host factors involved in maintaining HIV-1 latency.
• To elucidate the role of m⁶A-dependent mechanisms in HIV-1 gene silencing.
• To explore RBM39 as a potential therapeutic target for HIV-1 eradication.

Main Methods:

• Proteomic analysis to identify RNA-binding proteins associated with HIV-1 latency.
• Functional assays to assess the impact of RBM39 on viral gene expression and latency.
• In vitro studies using cell models and primary cells from people living with HIV-1 (PLWH).

Main Results:

• RBM39 acts as a scaffold for an m⁶A-dependent silencing complex, including YTHDC1 and DDX5.
• This complex promotes Tat RNA decay, enforcing HIV-1 quiescence.
• Degradation of RBM39, using indisulam, reactivates latent HIV-1 and synergizes with existing LRAs.

Conclusions:

• RBM39 is a key regulator of HIV-1 latency through epitranscriptomic control of Tat RNA.
• Targeting RBM39 offers a novel strategy to overcome limitations of current shock and kill approaches for HIV-1 cure.
• The findings provide a new framework for understanding m⁶A-dependent viral gene regulation.