Upstream Stimulatory Factors Regulate HIV-1 Latency and Are Required for Robust T Cell Activation

Area of Science:

• Molecular Biology
• Immunology
• Virology

Background:

• HIV-1 expression is regulated by T cell receptor signaling pathways, involving Ras and transcription factors like RBF-2.
• RBF-2, composed of USF1, USF2, and TFII-I, binds to HIV-1 LTR elements (RBE3, RBE1) for transcriptional induction.
• TFII-I recruits TRIM24 for transcriptional elongation, but the roles of USF1 and USF2 remain unclear.

Purpose of the Study:

• To investigate the distinct roles of USF1 and USF2 in HIV-1 expression.
• To explore the cooperative function of USF1 and USF2 in T cell activation and HIV-1 regulation.

Main Methods:

• Genetic deletion of USF1 and USF2 in T cells.
• RNA sequencing (RNA-seq) analysis of knockout T cell lines.
• Analysis of HIV-1 expression and T cell activation markers.

Main Results:

• Deletion of USF2, but not USF1, inhibited HIV-1 expression.
• Loss of USF2 reduced USF1 protein levels without affecting USF1 mRNA.
• USF1 and USF2 cooperatively regulate gene expression upon T cell stimulation (PMA/ionomycin).
• Knockout of either USF1 or USF2 impaired T cell activation.

Conclusions:

• USF2 is critical for HIV-1 expression, whereas USF1 is not.
• Cooperative function of USF1 and USF2 is essential for robust T cell inflammatory responses.
• These findings highlight distinct roles for USF1/USF2 in viral replication and host immunity.