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 Myh6 -MerCreMer with TRIM28 f/f and SETDB1 f/f 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 N 6 -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.