HIV-1 Vpr orchestrates ciTRAN upregulation through TGF-β induction.

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Circular RNA (circRNA) expression is prevalent in HIV-1 infected cells, but its interaction with cellular signaling pathways is not well understood.
• The role of specific circRNAs in HIV-1 pathogenesis requires further elucidation.

Purpose of the Study:

• To investigate the link between HIV-1 infection, circRNA expression, and cellular signaling pathways.
• To identify the mechanisms regulating circRNA production during HIV-1 infection.

Main Methods:

• Analysis of circRNA expression in HIV-1 infected cells.
• Investigating the role of HIV-1 Vpr protein in TGF-β production and circRNA upregulation.
• SMAD2/3 recruitment assays to the SMARCA5 promoter.
• Functional assays to determine the importance of SMAD binding motifs.
• Assessing the impact of TGF-β stimulation and TGFBR1 inhibition on ciTRAN and viral gene expression.

Main Results:

• HIV-1 Vpr induces TGF-β production, leading to the upregulation of the proviral circRNA ciTRAN (encoded by SMARCA5).
• SMAD2/3 is recruited to the SMARCA5 promoter in a Vpr-dependent manner, crucial for ciTRAN upregulation.
• The TGF-β-SMAD signaling pathway, along with QKI protein, regulates ciTRAN biogenesis and SMARCA5 mRNA expression.
• Inhibition of TGFBR1 reduces Vpr-mediated ciTRAN and viral gene expression.

Conclusions:

• The TGF-β-SMAD axis plays a critical role in regulating ciTRAN expression during HIV-1 infection.
• ciTRAN upregulation, mediated by TGF-β, may influence HIV-1 replication.
• Targeting the TGF-β signaling pathway offers a potential strategy to modulate HIV-1 replication.