Human Endogenous Retroviruses Drive Type-I Interferon Signaling activation in Early Rheumatoid Arthritis

Differentially expressed HERVs regulate adjacent ISGs expression by providing cis-regulatory elements. Moreover, excessive cytoplasmic HERVs trigger a type I interferon (IFN-I) response through the dsRNA-RIG-I-IRF3-IFN-I axis.

Targeting endogenous retroviruses exhibited potential therapeutic benefits in both CIA mouse models and RA patient-derived ex vivo models. Specifically, the IFN-I inducible HERV.MLT2B2, a novel primate-specific retroelement, acts as a key driver of the antiviral gene IFI44L, establishing a positive feedback loop that amplifies IFN-I signaling.