An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes
- PMID: 28878130
- PMCID: PMC5621895
- DOI: 10.1172/jci.insight.94387
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.
Keywords: Autoimmunity; Beta cells; Diabetes; Endocrinology; Innate immunity.
Conflict of interest statement
Figures
![Figure 1](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5621895/bin/jciinsight-2-94387-g001.gif)
![Figure 2](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5621895/bin/jciinsight-2-94387-g002.gif)
![Figure 3](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5621895/bin/jciinsight-2-94387-g003.gif)
![Figure 4](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5621895/bin/jciinsight-2-94387-g004.gif)
![Figure 5](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5621895/bin/jciinsight-2-94387-g005.gif)
![Figure 6](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5621895/bin/jciinsight-2-94387-g006.gif)
Similar articles
-
A new therapeutic approach for type 1 diabetes: Rationale for GNbAC1, an anti-HERV-W-Env monoclonal antibody.Diabetes Obes Metab. 2018 Sep;20(9):2075-2084. doi: 10.1111/dom.13357. Epub 2018 Jun 10. Diabetes Obes Metab. 2018. PMID: 29749030 Review.
-
Human Endogenous Retroviruses and Type 1 Diabetes.Curr Diab Rep. 2019 Nov 21;19(12):141. doi: 10.1007/s11892-019-1256-9. Curr Diab Rep. 2019. PMID: 31754894 Free PMC article. Review.
-
The envelope glycoprotein of human endogenous retrovirus HERV-W induces cellular resistance to spleen necrosis virus.Arch Virol. 2003 Apr;148(4):659-75. doi: 10.1007/s00705-002-0960-x. Arch Virol. 2003. PMID: 12664292
-
Anti-HERV-WEnv antibodies are correlated with seroreactivity against Mycobacterium avium subsp. paratuberculosis in children and youths at T1D risk.Sci Rep. 2019 Apr 18;9(1):6282. doi: 10.1038/s41598-019-42788-5. Sci Rep. 2019. PMID: 31000760 Free PMC article.
-
An N-terminally truncated envelope protein encoded by a human endogenous retrovirus W locus on chromosome Xq22.3.Retrovirology. 2010 Aug 24;7:69. doi: 10.1186/1742-4690-7-69. Retrovirology. 2010. PMID: 20735848 Free PMC article.
Cited by
-
Mechanistic regulation of HERV activation in tumors and implications for translational research in oncology.Front Cell Infect Microbiol. 2024 Feb 6;14:1358470. doi: 10.3389/fcimb.2024.1358470. eCollection 2024. Front Cell Infect Microbiol. 2024. PMID: 38379771 Free PMC article. Review.
-
Deletion of Vβ3+CD4+ T cells by endogenous mouse mammary tumor virus 3 prevents type 1 diabetes induction by autoreactive CD8+ T cells.Proc Natl Acad Sci U S A. 2023 Dec 5;120(49):e2312039120. doi: 10.1073/pnas.2312039120. Epub 2023 Nov 28. Proc Natl Acad Sci U S A. 2023. PMID: 38015847 Free PMC article.
-
Preliminary Evidence of the Differential Expression of Human Endogenous Retroviruses in Kawasaki Disease and SARS-CoV-2-Associated Multisystem Inflammatory Syndrome in Children.Int J Mol Sci. 2023 Oct 11;24(20):15086. doi: 10.3390/ijms242015086. Int J Mol Sci. 2023. PMID: 37894766 Free PMC article.
-
Transgenic expression of the HERV-W envelope protein leads to polarized glial cell populations and a neurodegenerative environment.Proc Natl Acad Sci U S A. 2023 Sep 19;120(38):e2308187120. doi: 10.1073/pnas.2308187120. Epub 2023 Sep 11. Proc Natl Acad Sci U S A. 2023. PMID: 37695891 Free PMC article.
-
SARS-CoV-2 awakens ancient retroviral genes and the expression of proinflammatory HERV-W envelope protein in COVID-19 patients.iScience. 2023 May 19;26(5):106604. doi: 10.1016/j.isci.2023.106604. Epub 2023 Apr 7. iScience. 2023. PMID: 37091988 Free PMC article.
References
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases