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

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

doi:10.1172/jci.insight.94387

Cited by 72 publications

(89 citation statements)

References 64 publications

(96 reference statements)

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“…Further analysis and promoter activity assays on the 5′ LTR of HERV‐HX demonstrated that a 17‐bp unique sequence within the 5′ U3 region contributed pivotally to the transcriptional activity of HERV‐HX . Although no exact chromosomal locations could be obtained for the X‐linked HERV‐H elements reported by Alves et al and Wentzensen et al we infer that these are the same one as HERV‐HX according to the rough chromosomal location and expression pattern. The functional importance of HERV‐HX, transcribing in a nonspliced format, needs further investigation.…”

Section: Introductionmentioning

confidence: 71%

“…16 HERV-W env gene products have also been detected in plasma of schizophrenia and bipolar disorders patients. 17,18 Recently, Levet et al demonstrated that HERV-W env expression was significantly upregulated in patients suffering from type 1 diabetes, 19 suggesting new therapies for type 1 diabetes. 20 Besides HERV-W, single-nucleotide polymorphisms (SNPs) around HERV-Fc1 showed a highly significant association with multiple sclerosis.…”

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confidence: 99%

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Expressional activation and functional roles of human endogenous retroviruses in cancers

Zhang

Liang

Zheng

2019

Reviews in Medical Virology

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Summary Human endogenous retroviruses (HERVs) are widely believed to be remnants of ancestral germ line infections by exogenous retroviruses. Although HERVs are deemed as “nonfunctional DNAs” due to loss of most of their viral protein coding capacity during evolution as part of the human genome, cumulative evidences are showing the expressional activation and potential roles of HERVs in diseases especially cancers. Work by other researchers and us has observed the dysregulation of HERVs in cancers, identified new HERV‐related genes, and revealed their potential importance in cancer development. Here, we summarized the current knowledge on the mechanisms of the expressional activation and functional roles of HERVs, with a focus on the H family HERV (HERV‐H), in carcinogenesis. HERV expression is regulated by external chemical or physical substances and exogenous virus infection, as well as host factors such as epigenetic DNA methylation, transcription factors, cytokines, and small RNAs. Diverse roles of HERVs have been proposed by acting in the forms of noncoding RNAs, proteins, and transcriptional regulators during carcinogenesis. However, much remains to be learnt about the contributions of HERVs to human cancers. More investigation is warranted to elucidate the functions of these “fossil remnants” yet important viral DNAs in the human genome.

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Section: Introductionmentioning

confidence: 71%

mentioning

confidence: 99%

Expressional activation and functional roles of human endogenous retroviruses in cancers

Zhang

Liang

Zheng

2019

Reviews in Medical Virology

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“…In addition, we discuss novel HERV-targeted therapeutic avenues that are starting to be evaluated in MS and ALS. Moreover, HERVs have also been associated with other diseases such as schizophrenia and bipolar disorder [10], as well as with type 1 diabetes [11], but much less data are available for these disorders.…”

Section: Keys To Understanding the Etiopathogenesis Of Inflammatory Amentioning

confidence: 99%

Human Endogenous Retroviruses in Neurological Diseases

Küry

Nath

Créange

et al. 2018

Trends in Molecular Medicine

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235

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The causes of multiple sclerosis and amyotrophic lateral sclerosis have long remained elusive. A new category of pathogenic components, normally dormant within human genomes, has been identified: human endogenous retroviruses (HERVs). These represent ∼8% of the human genome, and environmental factors have reproducibly been shown to trigger their expression. The resulting production of envelope (Env) proteins from HERV-W and HERV-K appears to engage pathophysiological pathways leading to the pathognomonic features of MS and ALS, respectively. Pathogenic HERV elements may thus provide a missing link in understanding these complex diseases. Moreover, their neutralization may represent a promising strategy to establish novel and more powerful therapeutic approaches.

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“…In parallel, a real‐time quantitative PCR study was conducted on PBMCs from 23 patients with T1D and from 26 blood donors without T1D. HERV‐W‐Env RNA was detected in 57% of patients with T1D vs 12% of controls …”

Section: Herv‐w‐env As a Potential Target And Biomarker For T1dmentioning

confidence: 99%

“…For this reason, the pathogenic effect of HERV‐W‐Env has been assessed in vitro on primary human Langerhans islets and on rat insulinoma cells INS1E. It has been shown that HERV‐W‐Env impairs insulin secretion by pancreatic β cells in a dose‐related fashion in pancreatic β cells of both species.…”

Section: Herv‐w‐env As a Potential Target And Biomarker For T1dmentioning

confidence: 99%

A new therapeutic approach for type 1 diabetes: Rationale for GNbAC1, an anti‐HERV‐W‐Env monoclonal antibody

Curtin

Bernard

Levet³

et al. 2018

Diabetes Obesity Metabolism

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We describe a newly identified therapeutic target for type 1 diabetes (T1D): an envelope protein of endogenous retroviral origin, human endogenous retrovirus W envelope (HERV-W-Env). HERV-W-Env was found to be detected in the blood of ~60% of patients with T1D and is expressed in acinar pancreatic cells of 75% of patients with T1D at post mortem examination. Preclinical experiments showed that this protein displays direct cytotoxicity on human β-islet cells. In vivo HERV-W-Env impairs the insulin and glucose metabolism in transgenic mice expressing HERV-W-Env. GNbAC1, an IgG4 monoclonal antibody, has been developed to specifically target HERV-W-Env and to neutralize the effect of HERV-W-Env in vitro and in vivo. GNbAC1 is currently in clinical development for multiple sclerosis and > 300 subjects have been administered with GNbAC1 so far. GNbAC1 is now being tested in T1D in the RAINBOW-T1D study, which is a randomized placebo-controlled study with the objective of showing the safety and pharmacodynamic response of GNbAC1 in patients who have had T1D with a maximum of 4 years' duration. GNbAC1 is being tested vs placebo at the dose of 6 mg/kg in 60 patients during six repeated administrations for 6 months; a 6-month open-label extension will follow. The primary endpoint is to assess safety, and secondary endpoints are the pharmacodynamic responses to GNbAC1. GNbAC1 targeting HERV-W-Env is currently in clinical development in T1D, with the first safety and pharmacodynamic study. If the study results are positive, this may open the door to the development of an innovative non-immunomodulatory disease-modifying treatment for T1D.

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

Cited by 72 publications

References 64 publications

Expressional activation and functional roles of human endogenous retroviruses in cancers

Expressional activation and functional roles of human endogenous retroviruses in cancers

Human Endogenous Retroviruses in Neurological Diseases

A new therapeutic approach for type 1 diabetes: Rationale for GNbAC1, an anti‐HERV‐W‐Env monoclonal antibody

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