Targeting viral dsRNA for antiviral prophylaxis

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Most viruses produce double-stranded RNA (dsRNA) during infection.
• Viruses have evolved mechanisms to evade host antiviral responses targeting dsRNA.
• Existing antiviral strategies are often circumvented by viral countermeasures.

Purpose of the Study:

• To develop a broad-spectrum antiviral strategy by antagonizing viral countermeasures.
• To create novel dsRNA-dependent caspase recruiters (dsCAREs) that bypass viral evasion tactics.
• To leverage dsRNA as a target for rapid antiviral prophylaxis.

Main Methods:

• Engineered dsRNA-binding proteins to recruit apoptosis signaling pathways, creating dsCAREs.
• Tested dsCAREs' antiviral activity against Adenovirus (dsDNA) and Vesicular Stomatitis Virus (negative-stranded RNA) in HEK293 cells.
• Evaluated dose-dependent effects and the necessity of dsRNA binding and apoptosis activation for antiviral function.

Main Results:

• dsCAREs demonstrated significant suppression of viral infection starting at 0.1 μg/ml, with an EC(50) of approximately 0.2 μg/ml.
• Antiviral activity was specific to infected cells, with no detectable effect on uninfected cells.
• Both dsRNA binding and apoptosis activation capabilities of dsCAREs were crucial for their antiviral efficacy.

Conclusions:

• dsRNA serves as a viable virus-associated molecular pattern for broad and rapid antiviral interventions.
• dsCAREs represent a promising therapeutic strategy by hijacking viral dsRNA to induce apoptosis and inhibit infection.
• The engineered dsCARE system offers a novel approach to combat diverse viral infections by bypassing common viral evasion mechanisms.