Targeting Endogenous Retroviruses as a Novel Immunometabolic Therapy: HERV-K Activation in Human Tissues and Proof-of-Concept Rescue in Diabetic Mice

Introduction and Objective: Endogenous retroelements - including human endogenous retrovirus-K (HERV-K) and murine orthologues - emerging as unrecognized regulators of inflammation, and tissue dysfunction. We present new evidence that HERV-K is activated in human metabolic tissues under stress and provide the first in vivo proof-of-concept that targeting ERV-targeted immunotherapy can improve metabolic dysfunction. Methods: Human studies include: (1) HERV-K RNA expression in lean vs MASH liver spheroids; (2) HERV-K activation in skeletal muscle RNA-seq datasets from people with T2D vs normal glucose tolerance; and (3) primary adipocytes and β cells exposed to metabolic and inflammatory stressors, measuring HERV-K and senescence markers. In mice, ERV-based immunotherapies were tested in two C57BL/6J models: a dexamethasone/streptozotocin HFD model (DS-HFD), and a fast-food mimicking diet model (FFMD) under thermoneutrality, assessing glucose tolerance, insulin sensitivity, weight, LCN2, senescence, ERV expression, and ERV-specific immunity. Results: Specific HERV-K loci were upregulated in MASH vs lean liver and in T2D skeletal muscle vs. lean controls. In stressed adipocytes, HERV-K expression increased alongside β-gal activity, with significant correlations between HERV-K and senescence. In DS-HFD, IAPE immunotherapy improved glucose tolerance, reduced insulin resistance, limited weight gain, lowered LCN2, decreased p21 and ERV transcripts in metabolic tissues, and induced ERV-specific T- and B-cell responses. In FFMD, ERV immunization improved glucose tolerance. Conclusion: These data provide evidence that HERV-K is activated in human metabolic tissues under stress and that targeting orthologous ERVs in mice improve metabolic outcomes. Accordingly, ERV-directed immunotherapy emerges as a novel potential approach for treating metabolic disease and T2D. Disclosure: D.B. Andersen: None. N. Skeltved: None. T.O. Garde-Due: None. I. Ausina Gutiérrez: None. G.M. González: None. A. Andersson: None. E.S. Engdal: None. E. Ragonnaud: None. K.V. Grunddal: Consultant; Current; HERVolution Therapeutics. P. Holst: None. Funding: Novo Nordisk Foundation (NNF23OC0087224)