An Aberrant Resurgence of Endogenous Retroviruses Prompts Myocarditis and Heart Failure.

Background: Endogenous retroviruses (ERVs) occupy >8% of the human genome. Aberrant resurgence of ERVs has been implicated recently in several critical pathologies. However, the possible incidence and role of ERV resurgence in heart failure (HF), a leading cause of global morbidity and mortality, remain unexplored.

Methods: We established a total RNA sequencing analyzing pipeline to assess the ERV occurrence in human and murine HF models. We generated 2 myocardium-specific mouse lines by crossing -MerCreMer with TRIM28 and SETDB1 mice to identify the molecular regulators of ERV resurgence and the downstream pathways in the heart. We evaluated ERV expression by total RNA sequencing, reverse transcription-quantitative polymerase chain reaction and RNA fluorescence in situ hybridization. We restrained ERV activation by overexpressing TRIM28 (tripartite motif-containing 28) using adeno-associated virus serotype 9. The therapeutic potential of the ERV-mediated inflammatory pathway was tested in a myocardial ischemia/reperfusion model.

Results: ERVs, particularly class I ERVs, were prominently activated in multiple cross-species models of HF. Depletion of TRIM28, an epigenetic repressor, attenuated the epigenetic surveillance of trimethylation at lysine 9 of histone H3 and -methyladenosine, leading to the activation of ERVs in the failing heart. This ERV activation stimulated the antiviral innate immune pathways of TLR7/9 (Toll-like receptor 7/9) and NF-κB and lead to myocarditis and acute HF. Furthermore, restraining ERV activation and ERV-mediated innate immune responses by either adeno-associated virus serotype 9-mediated TRIM28 expression or a small-molecule TLR7/9 inhibitor improved heart function and alleviated HF in an ischemia/reperfusion model.

Conclusions: ERV resurgence is a specific molecular trait of HF, driven by TRIM28 depletion in cardiomyocytes. ERV resurgence activates the innate immune TLR7/9-NF-κB pathway and induces myocarditis and HF. Inception of ERVs and the ERV-mediated immune pathway confers cardiac protection. These results identify TRIM28-ERV-TLR7/9-NF-κB as a target for therapeutic management of myocarditis and HF.