Qualitative Differences Between the IFNα subtypes and IFNβ Influence Chronic Mucosal HIV-1 Pathogenesis

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Type I interferons (IFN-Is) are crucial innate antiviral cytokines.
• IFN-Is signal through the IFN-I receptor (IFNAR) to induce IFN-stimulated genes (ISGs).
• The role of IFN-Is in HIV-1 infection shifts from protective in acute stages to potentially pathogenic in chronic stages.

Purpose of the Study:

• To investigate qualitative differences in the interferomes induced by various IFNα subtypes and IFNβ.
• To explore the differential roles of IFN-Is in the context of chronic HIV-1 infection in the gut.

Main Methods:

• Ex vivo treatment of primary gut CD4 T cells with normalized IFN-Is.
• Comparison of gene expression profiles (interferomes) induced by different IFNα subtypes and IFNβ.
• Analysis of gene expression in gut biopsies from HIV-1-uninfected individuals and persons with HIV-1 (PWH).

Main Results:

• Despite shared induction of canonical antiviral ISGs, distinct IFNα subtypes elicited unique sets of IFN-regulated genes, demonstrating qualitative differences.
• IFNβ induced a broader interferome compared to individual IFNα subtypes.
• In PWH, core ISGs associated with inflammation and immune exhaustion were elevated, while IFNβ-specific ISGs linked to protein translation and anti-inflammation were downregulated.

Conclusions:

• Qualitative differences exist in the interferome induced by diverse Type I interferons.
• Elevated IFNβ and associated ISGs in the gut of PWH may contribute to HIV-1 pathogenesis.
• IFNβ-specific ISGs' downregulation suggests a potential mechanism for immune dysregulation in chronic HIV-1 infection.