One-Step Multiplex PCR Reveals Selective Activation of Immunostimulatory Human Endogenous Retroviruses and Epigenetic Imbalance in Systemic Lupus Erythematosus

TL;DR

This study finds that specific human endogenous retroviruses are selectively activated in lupus patients, linked to immune and epigenetic changes.

Contribution

The study identifies selective activation of HERV-W and its link to interferon signaling in systemic lupus erythematosus.

Findings

HERV-K and HERV-W are significantly overexpressed in lupus patients.

HERV-W env transcripts and Syncytin-1 are markedly increased in SLE.

Reduced TRIM28 and increased SETDB1 suggest epigenetic imbalance in lupus.

Abstract

Systemic lupus erythematosus (SLE) is characterized by chronic immune activation, enhanced type I interferon signaling, and epigenetic dysregulation, conditions that may promote the reactivation of human endogenous retroviruses (HERVs). Whether HERV activation in SLE is global or selective, however, remains unclear. We analyzed the expression of HERV-H, HERV-K, and HERV-W, along with the HERV-derived envelope genes Syncytin-1 and Syncytin-2, in samples from lupus patients and healthy controls. In parallel, we assessed the expression of the epigenetic repressors TRIM28 and SETDB1. HERV-H expression was comparable between groups, whereas HERV-K and HERV-W were significantly overexpressed in lupus patients. Syncytin-1 and HERV-W env transcripts were markedly increased in SLE, while Syncytin-2 expression was unchanged. Lupus patients showed reduced TRIM28 and increased SETDB1 expression, consistent with altered regulation of HERV repression pathways. Notably, HERV-H and HERV-W pol expression correlated with the type I interferon score, suggesting an association between interferon signaling and selective HERV activation. These findings indicate that SLE is associated with the selective activation of immunostimulatory HERV families, particularly HERV-W. The observed associations with interferon signaling suggest that HERV-W-related transcripts may represent disease-associated molecular signatures, warranting further mechanistic investigation.

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