Single amino acid changes that render human IFN-alpha 2 biologically active on mouse cells

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• Human interferon-alpha (IFN-alpha) subtypes possess varying antiviral specificities across species.
• Differences in amino acid sequences between IFN-alpha 1 and IFN-alpha 2 contribute to their distinct biological activities.

Purpose of the Study:

• To identify specific amino acid residues responsible for differential antiviral activity of human IFN-alpha subtypes on murine cells.
• To elucidate the role of these residues in potential interactions with the mouse interferon receptor.

Main Methods:

• Hybrid scanning and site-directed mutagenesis techniques were employed.
• Comparative analysis of antiviral activity of modified IFN-alpha 2 variants on murine cells.
• Inference of receptor-binding site involvement based on functional alterations.

Main Results:

• Three specific amino acid positions (121, 125, and 132) in IFN-alpha 2 were identified as critical.
• Individual or combined substitution of these residues with their IFN-alpha 1 counterparts resulted in up to a 400-fold change in antiviral activity on mouse cells.
• These modifications significantly altered the species-specific antiviral efficacy.

Conclusions:

• The identified residues in IFN-alpha 2 are crucial determinants of its antiviral activity on murine cells.
• These residues are likely involved in direct binding interactions with the mouse interferon receptor.
• Understanding these molecular interactions can inform the development of targeted interferon-based therapies.