An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes
Sandrine Levet, … , Jean-Louis Touraine, Hervé Perron
Sandrine Levet, … , Jean-Louis Touraine, Hervé Perron
Published September 7, 2017
Citation Information: JCI Insight. 2017;2(17):e94387. https://doi.org/10.1172/jci.insight.94387.
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Research Article Endocrinology

An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes

Abstract

Human endogenous retroviruses (HERVs), remnants of ancestral viral genomic insertions, are known to represent 8% of the human genome and are associated with several pathologies. In particular, the envelope protein of HERV-W family (HERV-W-Env) has been involved in multiple sclerosis pathogenesis. Investigations to detect HERV-W-Env in a few other autoimmune diseases were negative, except in type-1 diabetes (T1D). In patients suffering from T1D, HERV-W-Env protein was detected in 70% of sera, and its corresponding RNA was detected in 57% of peripheral blood mononuclear cells. While studies on human Langerhans islets evidenced the inhibition of insulin secretion by HERV-W-Env, this endogenous protein was found to be expressed by acinar cells in 75% of human T1D pancreata. An extensive immunohistological analysis further revealed a significant correlation between HERV-W-Env expression and macrophage infiltrates in the exocrine part of human pancreata. Such findings were corroborated by in vivo studies on transgenic mice expressing HERV-W-env gene, which displayed hyperglycemia and decreased levels of insulin, along with immune cell infiltrates in their pancreas. Altogether, these results strongly suggest an involvement of HERV-W-Env in T1D pathogenesis. They also provide potentially novel therapeutic perspectives, since unveiling a pathogenic target in T1D.

Authors

Sandrine Levet, Julie Medina, Julie Joanou, Amandine Demolder, Nelly Queruel, Kevin Réant, Matthieu Normand, Marine Seffals, Julie Dimier, Raphaële Germi, Thomas Piofczyk, Jacques Portoukalian, Jean-Louis Touraine, Hervé Perron

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Figure 6

Current working model.

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Current working model. This diagram illustrates the current working mode...
This diagram illustrates the current working model in which the present study is integrated. Data presented demonstrate that HERV-W-Env protein is expressed in T1D patients and particularly in their pancreas (Figure 1), where it may promote β cell dysfunction (Figure 5) and macrophages recruitment (Figure 3), possibly leading to hyperglycemia and decrease levels of insulin (Figures 4 and 5). As reported by other studies, HERV-W-Env displays other pathogenic properties that may be relevant in T1D pathogenesis. In particular, HERV-W-Env promotes autoimmunity (23) and impairs TLR4+ cells such as endothelial cells (49) and Schwann cells (50), both of which are associated with major T1D comorbidities. The underlying question is why the HERV-W-env gene has been transcriptionally activated and translated into a pathogenic protein. An explanation relies upon its transactivation and epigenetic dysregulation by infectious agents, as it has already been demonstrated (33, 60, 61). In T1D, the question of such dysregulation by enterovirus is raised (12), as well as the role of EBV (62). This diagram illustrates how, in a global pathogenic cascade leading to the disease, HERV-W-Env expression is placed at a crucial position, between multiple environmental factors operating in genetically susceptible individuals and multiple clinical outcomes. This positioning provides a rationale for the neutralization of HERV-W-Env as a therapeutic target in T1D. Within this framework, GNbAC1 — a humanized monoclonal IgG4 antibody neutralizing HERV-W-env — is currently tested in a phase IIa clinical trial in T1D patients (NCT03179423).