Title of project

Harnessing Endogenous Retrovirus-Based Immunotherapy for Metabolic Syndrome Treatment (Treatment HERO)

Abstract

The project proposes that targeting endogenous retroviruses (ERVs) through immunotherapy may provide a novel therapeutic strategy to limit the progression of Type 2 Diabetes (T2D) by reducing cellular senescence. T2D, a late-stage manifestation of Metabolic Syndrome (MetS), is driven by chronic insulin resistance, low-grade inflammation, and progressive β-cell dysfunction. While current interventions can often alleviate early symptoms, they require lifelong use and fail to halt advanced T2D due to progressive β-cell dysfunction, highlighting the need for more effective, mechanism-based strategies. ERVs, remnants of ancient viral infections, are reactivated under cellular stress, and drive inflammation and cellular senescence in metabolically active tissues, thereby driving metabolic dysfunction. As HERV-K family and its murine orthologues, Intracisternal-A-Particles related Envelope (IAPE), mouse mammary tumor virus (MMTV), and murine leukemia virus (MLV), are key contributors in senescence, they make interesting targets in the treatment of metabolic dysfunction. This project will develop optimized viral vector-based immunotherapies targeting murine ERVs, specifically IAPE and MMTV, engineered with novel mutations in the envelope´s immunosuppressive domain (ISD) to break immune tolerance. In vitro studies will assess the immunotherapies’ inflammatory potential; in vivo models will evaluate effects on T cell activation, insulin resistance, glucose metabolism, and weight gain under a novel fast-food mimicking diet (FFMD) that together with isothermal housing conditions triggers T2D and hepatic steatohepatitis in mice. Mechanistic insights will be further explored via immune cell depletion experiments, transcriptomics, metabolic immunogenic profiling, and cellular energetics, with inclusion of comparative human tissue datasets. The project will validate the robustness of ERV immunotherapies in T2D animals, ultimately aiming to justify appropriately targeted interventions to treat T2D in humans.