SRSF1 acts as an IFN-I-regulated cellular dependency factor decisively affecting HIV-1 post-integration steps

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Efficient HIV-1 replication relies on host cell factors, including serine/arginine-rich splicing factors (SRSFs).
• Type I interferons (IFN-I) induce IFN-stimulated genes (ISGs) and may repress other genes (IRepGs) affecting viral replication.
• Limited knowledge exists on IRepGs influencing HIV-1 infection and host dependency factors.

Purpose of the Study:

• To investigate the role of SRSF1, a splicing factor, in HIV-1 replication.
• To determine if SRSF1 levels are modulated by IFN-I during HIV-1 infection.
• To elucidate the mechanisms by which SRSF1 influences HIV-1 post-integration steps.

Main Methods:

• Quantified SRSF1 levels in cells from HIV-1 infected individuals (LPMCs, PBMCs).
• Assessed SRSF1 expression in HIV-1 susceptible cell lines and macrophages upon IFNα treatment.
• Utilized 4sU labeling to study IFN-mediated SRSF1 regulation at the RNA level.
• Performed SRSF1 knockdown and overexpression experiments to evaluate effects on HIV-1 replication, Vif mRNA, LTR activity, and viral production.

Main Results:

• HIV-1 infection and ISG induction correlated with decreased SRSF1 levels in vivo.
• IFNα treatment repressed SRSF1 expression in vitro at the early RNA level.
• SRSF1 knockdown increased total viral RNA but reduced Vif mRNA; however, it enhanced replication in the presence of APOBEC3G.
• SRSF1 overexpression impaired HIV-1 post-integration steps, including LTR transcription and virus production.

Conclusions:

• SRSF1 levels are modulated by IFN-I during HIV-1 infection.
• SRSF1 acts as a crucial cellular dependency factor regulating HIV-1 post-integration steps.
• Balanced SRSF1 levels are essential for efficient HIV-1 replication.