HHV-6 “Junk” DNA Contributing to the Development of T1D
By: Tiffany Richardson
The many factors in the initiation, development, and pathogenesis of Type 1 diabetes (T1D) contributes to difficulties in defining and treating T1D fully. There is increasing evidence relating viral infection to the etiopathogenesis and disease course of T1D. From millions of years ago up until today, human endogenous retroviruses (HERVs) have been infecting germ cells resulting in an integration of HERV genetic material into subsequent generations. Over time HERV sequences are transported and multiplied throughout the genome. Now, about 8% of the human genome is composed of HERV gene copies. Due to the inactivation and silencing of many HERV sequences, the field believed that these sequences were “junk DNA”. But some HERV genes are beginning to be taken out of scientific garbage cans and associated to both physiology and pathological processes .
Viral infection and inflammation can activate HERV sequences in humans which may trigger downstream processes related to autoimmunity initiation. HERVs have been implicated in various autoimmune diseases such as Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS). Autoimmunity seen in T1D, therefore, may be in part caused by viral HERV activation. Additionally, inflammation during the course of autoimmunity can activate HERV sequences which may provide positive feedback for pro-inflammatory cytokine release. Initial immune attack as well as residual inflammation has been detailed in T1D pathogenesis. Therefore, viral-mediated activation of HERV sequences could help to link the T1D viral hypothesis to initiation and progression of T1D .
HHV-6 Expression is Increased in T1D Pancreata
Human Herpesvirus 6 (HHV-6) has been shown to activate endogenous HERV gene transcription after viral receptor binding. HHV-6 has two variants, HHV-6A and HHV6B. The HHV6 Foundation states that “HHV-6B infects nearly 100% of human beings, typically before the age of three” . Sabouri and colleagues explored HHV-6 expression in human pancreatic tissue from non-diabetic (control), auto-antibody (AAB+), and T1D donors . Check out their findings below:
- HHV-6 RNA and protein were found in non-diabetic, AAB+, and T1D tissue.
- HHV-6 glycoprotein B (gB) was expressed to a greater extent in islets and exocrine tissue of T1D pancreata.
- Glycoproteins are used by HHV-6 for viral entry into target cells
- There was no correlation between gB expression, MHC class I expression, and CD8+ T cell islet infiltration. Therefore, gB expression may be more related to an increased susceptibility of T1D pancreata to HHV-6 infection in general.
The presence of HHV-6 in pancreatic tissue in general and in T1D emphasize the ubiquity of HHV-6 infection while also showing that HHV-6 can infect these cell types. Because HHV-6 can lay dormant and become reactivated at later stages of life, HHV-6 infection and/or reactivation may be implicated in HERV-derived T1D pathogenesis. HHV-6 infection seems to also occur very early on in life which may predispose individuals to T1D.
**These results extend from a previous publication in 2017 that observed similar HHV-6 expression phenotypes .
The Takeaway: The higher expression of HHV-6 glycoprotein B expression in T1D pancreatic islets may lead to a ripe environment for autoimmunity initiation. Therapeutics targeting HERV sequences have been developed for other autoimmune diseases and have shown promising results. Garnering a greater understanding for HHV-6 activation of HERV sequences may open a new avenue for treating T1D before disease initiation.
- Levet, S., Charvet, B., Bertin, A., Deschaumes, A., Perron, H., & Hober, D. (2019). Human Endogenous Retroviruses and Type 1 Diabetes. Current diabetes reports, 19(12), 141. https://doi.org/10.1007/s11892-019-1256-9.
- What Is HHV-6? https://hhv-6foundation.org/what-is-hhv-6.
- Sabouri, S., Benkahla, M., Kiosses, W., et al. (2020). Human herpesvirus-6 is present at higher levels in the pancreatic tissues of donors with type 1 diabetes, 107. https://doi.org/10.1016/j.jaut.2019.102378.
- Ericsson, M. and Skog, O. (2017). Presence of Human Herpesvirus 6B in Pancreas Subjects With and Without Type 1 Diabetes. Pancreas, 46(10). https://doi.org/10.1097/MPA.0000000000000927.