Type-2-diabetes is characterized by progressive metabolic stress and accumulation of senescent cells in key metabolic tissues, such as the pancreas, adipose tissue, and liver. Cellular senescence - an irreversible growth-arrested, and pro-inflammatory cell state can lead to induction of endogenous retrovirus (ERV) expression, which can also trigger cellular senescence. This possibly implies that a self-reinforcing ERV-senescence axis contributes to the metabolic decline and T2D. Here we developed and tested a mouse endogenous retrovirus (muERV) based active immunotherapy targeted at the most intact muERV, IAPE (Intracisternal A-type Particles elements with an Envelope) to eliminate cells expressing muERVs and senescence associated proteins in a mouse model of accelerated diabetes combining a high-fat diet (HFD) with dexamethasone (DEX) and streptozotocin (STZ) (DS-HFD). Immunized DS-HFD mice (DS-HFD + IAPE-Tx) showed increased B and T cell responses towards IAPE. Antisera generated using our IAPE-targeted active immunotherapy was used to confirm activation of IAPE expression in the murine β-cell line MIN-6, following both inflammatory (cytokines) and chemical stress (STZ and DEX). In Vivo, DS-HFD + IAPE-Tx mice showed reduced weight gain, improved fasting insulin-glucose homeostasis and oral glucose tolerance. They furthermore showed reduction in histomorphometry features consistent with steatosis, hepatocyte binucleation, reduced adipocyte size, and pancreatic islet senescence markers p16INK4a and p21Cip1/waf1, with a slight decrease in islet IAPE. Finally, we show activation of a human orthologue to IAPE, HERV-K, in cytokine-exposed isolated human pancreatic islets and EndoC-βH5 β-cells. Together, our results suggest that ERV antigens are expressed in metabolic disease models and may be targeted by immunotherapy to improve metabolic parameters, through a potential senolytic or senostatic-related but so far undefined mechanism.
