Researchers
Karen Giménez-Orenga, Eva Martín-Martinez, Elisa Oltra
Institutions
Catholic University of Valencia and Manises Hospital, Valencia, Spain
Publication
Pathogens, 2024; 13(9):751
Funding
ME Research UK
Key findings
Prof. Elisa Oltra and colleagues have published more results from their ME Research UK-funded study looking at the role of human endogenous retrovirus (HERV) in ME/CFS. They found increased levels of a virus called TTMV9 in people with ME/CFS and activated HERVs, and suggest that it has potential as a biomarker for the disease in this subgroup of patients. While TTMV9 is normally found in humans, high levels could indicate abnormal immunity, and the researchers found associations between TTMV9 and altered HERV and immunological profiles in these patients.
About the study
Human endogenous retroviruses (HERVs) are a family of viruses contained within the human genome – that is, their DNA has become part of our DNA and is passed on from generation to generation.
Most HERVs are thought to be inactive, but there is evidence that some may have a role in the development of diseases such as multiple sclerosis, type 1 diabetes and schizophrenia. They have also been proposed as potential triggers of ME/CFS.
Prof. Elisa Oltra and her team at the Catholic University of Valencia have been investigating the role of HERVs in ME/CFS, and in previous (still to be published) work they identified a subgroup of patients with activated HERVs. These may lead to an innate immune response, and the resulting flu-like symptoms and autoimmune problems that are characteristic of ME/CFS.
The group then turned to look at factors that might be linked to HERV activation, and which may therefore provide insight into the mechanisms underlying ME/CFS, as well as diagnostic markers for the disease.
What did they do?
In this study, Prof. Oltra and her colleagues explored the possibility that HERV activation in people with ME/CFS may be triggered by immunological disturbances caused by active viral infections.
They analysed viral RNA sequences in immune cells (peripheral blood mononuclear cells) extracted from blood samples from eight ME/CFS patients previously found to have activated HERVs. They also sampled people with fibromyalgia, those with fibromyalgia and ME/CFS, and healthy control subjects.
RNA is a molecule which uses the genetic information in DNA to build proteins, and some viruses have RNA as their main genetic material. These RNA viruses are responsible for many human diseases, including the common cold, influenza, COVID-19 and hepatitis C.
The researchers extracted RNA from the immune cells, and then used a high-density microarray and computer analyses to assess the expression levels of 289 viruses.
What did they find?
The viruses analysed represented several different families but, on the whole, expression levels of these virus families did not differ between the various subject groups.
However, when the researchers analysed individual viruses, they found increased RNA levels of the Torque Teno Mini Virus 9 (TTMV9) in the subgroup of ME/CFS patients with activated HERVs, compared with the other subject groups.
TTMV9 belongs to a family of viruses called anelloviruses, which are found very commonly in many tissues of the human body, but do not appear to have been linked previously with any diseases (although one study found a species of TTMV in patients with gum disease).
Interestingly, TTMV9 was the only member of the anellovirus family with increased RNA levels in this ME/CFS subgroup.
TTMV9 levels correlated with several other measures, including HERV levels and the expression of a number of immune-related genes.
The researchers also performed an analysis showing that TTMV9 RNA levels could discriminate well between the ME/CFS subgroup with activated HERVs and the other patient subgroups, indicating its potential value as a biomarker for this subgroup.
Limitations
It is worth noting that these analyses were performed in a relatively small number of subjects (particularly when divided into subgroups), and these findings would need to be confirmed in much larger numbers.
The researchers also highlight that there are a number of viruses that the microarrays they used are not able to detect, including some previously implicated in ME/CFS. And they will not have been able to take account of coinfections with bacteria or other microorganisms.
Conclusions
In summary, Prof. Oltra and colleagues have found increased levels of TTMV9 virus in people with ME/CFS and activated HERVs, and suggest that it has potential as a biomarker for the disease.
While TTMV9 is normally found in humans, high levels could indicate altered immunity, and the researchers found associations between TTMV9 and abnormal HERV and immunological profiles in these patients.
