Virus World

COVID-19 reactivated viruses that had become latent in cells following previous infections, particularly in people with chronic fatigue syndrome, also known as ME/CFS. This is the conclusion of a study from Linköping University in Sweden. The results, published in Frontiers in Immunology, contribute to our knowledge of the causes of the disease and prospects of reaching a diagnosis. Severe, long-term fatigue, post-exertional malaise, pain and sleep problems are characteristic signs of myalgic encephalomyelitis/chronic fatigue syndrome, “ME/CFS”. The causes of the condition are not known with certainty, although it has been established that the onset in most cases follows a viral or bacterial infection. The health of the person affected is not restored even after the original infection is resolved. Indeed – the condition is sometimes known by its alternative name: post-viral fatigue. Since the cause is not known, diagnostic tests have not been developed. “This patient group has been neglected. Our study now shows that objective measurements are available that show physiological differences in the body’s reaction to viruses between ME patients and healthy controls,” says Anders Rosén, professor emeritus in the Department of Biomedical and Clinical Sciences (BKV) at Linköping University, and leader of the study.  One theory that has been examined in several research studies is that a new infection can activate viruses that lie latent in the body’s cells after a previous infection. It has long been known that several herpes viruses, for example, can remain in a latent state in the body.

Latent viruses can be reactivated many years later and give rise to a new bout of disease. It has, however, been difficult to determine whether such reactivated viruses are involved in ME/CFS – until now. The extensive spread of the SARS-CoV-2 coronavirus during the COVID-19 pandemic has given researchers a unique opportunity to study what happens in people with ME/CFS during a mild virus infection and compare this with what happens in healthy controls. In collaboration with the Bragée Clinic in Stockholm, the research group initiated a study early in the pandemic. Ninety-five patients who had been diagnosed with ME/CFS and 110 healthy controls participated in the study. They provided blood and saliva samples on four occasions during one year. The researchers analysed samples for antibodies against SARS-CoV-2 and latent viruses, and found a special fingerprint of antibodies against common herpes viruses in saliva. One of these viruses was the Epstein-Barr virus (EBV), which has infected nearly everybody. Most people experience a mild infection during childhood. People who are infected with EBV in the teenage years can develop glandular fever, commonly called mononucleosis, and also known as “kissing disease”. The virus then remains in a latent condition in the body. The EBV virus may proliferate in situations in which the immune system is impaired, causing fatigue, an autoimmune responses, and increased risk of lymphoma, if allowed to continue. Approximately half of the participants were infected with SARS-CoV-2 during the first wave of the pandemic and developed mild COVID-19 (58% of those with ME/CFS and 41% of the control group). In more than one third of cases, infection had been asymptomatic, so the person had not been aware of the infection. After the SARS-CoV-2 infection had passed, however, the researchers detected specific antibodies in the saliva that suggested that three latent viruses had been strongly reactivated, one of them being EBV. The reactivation was seen both in patients with ME/CFS and in the control group, but was significantly stronger in the ME/CFS group.

Anders Rosén describes what happens as a domino effect: infection with a new virus, SARS-CoV-2, can activate other, latent, viruses in the body. The researchers suggest that this can, in turn, give rise to a chain reaction with an elevated immune response. This can have negative consequences, one of which is that the immune system attacks certain tissues, such as nerve tissue, in the body. Previous studies have also shown that the mitochondria, which produce energy in the cells, are affected, which suppresses the energy metabolism of people with ME/CFS. “Another important result from the study is that we see differences in antibodies against the reactivated viruses only in the saliva, not in the blood. This means that we should use saliva samples when investigating antibodies against latent viruses in the future,” says Anders Rosén. He points out that there is a great deal of overlap between the symptoms of ME/CFS and those of long COVID, which is experienced by around one third of patients who contract COVID-19. Exhaustion after light exercise, brain fog and unrefreshing sleep are common symptoms, while impaired lung capacity and abnormal senses of smell and taste are more specific for long COVID. The researchers believe that the results from the study can contribute to developing immunological tests to diagnose ME/CFS, and possibly also long COVID. “We now want to continue and carry out more detailed investigations into the immune response in ME/CFS, and in this way understand the differences between the antibody responses against latent viruses,” says Eirini Apostolou, principal research engineer, and lead author of the article. The study was financially supported by the Swedish Research Council, the Swedish Cancer Society and Linköping University. Some of the authors have financial interests in the Bragée Clinic.

Study cited published in Frontiers in Immunology (Oct. 20, 2022):

https://doi.org/10.3389/fimmu.2022.949787 

Genes from a virus that was stitched into the human genome thousands of years ago are active, producing proteins in the human brain and other tissues, according to researchers at the University of Washington School of Medicine and the Laval University School of Medicine in Quebec, Canada. Their finding might help explain why people who inherit this “fossil virus” appear to have a higher risk of developing neurodegenerative diseases such as multiple sclerosis and Alzheimer’s.

“There have been some reports that the virus, called human herpesvirus-6, can reactivate, but if it does, it’s rare,” said Dr. Alex Greninger, UW assistant professor of laboratory medicine. “What we wanted to know whether some of the virus’ individual genes were being turned on without full reactivation of the virus.”

The Journal of Virology published the article recently. Its lead authors were Vikas Peddu, a bioinformatician in the Greninger lab, and Isabelle Dubuc of Laval University. The project was led by Greninger and Louis Flamand, professor in the microbiology and immunology at Laval. The researchers were interested in two versions of human herpesvirus-6 (HHV-6) that can integrate into chromosomes and be inherited like any other human gene. HHV-6B causes the common childhood illness, roseola. This infection affects about 90 percent of children early in life, causing high fevers and rash. However, relatively little is known about the second virus, HHV-6A. After infection, both viruses can remain dormant in the body and reactivate later, particularly in people whose immune systems are suppressed.

In the new study, the researchers looked at a form of the virus that is not acquired by infection but which about one in a hundred people inherit as part of their genome. About 8 percent of human DNA comes from viruses inserted into our genomes in the distant past, in many cases into the genomes of our pre-human ancestors millions of years ago. Most of these viral genes come from retroviruses, RNA viruses that insert DNA copies of their own genes into our genomes when they infect cells. HHV-6 is unique because it is the only known human DNA herpesvirus that integrates into the human genome and can be routinely inherited. HHV-6’s genome may have been accidentally copied into the human genome because it has repeating DNA sequences that resemble those found in human chromosomes. In conducting the study, the investigators analyzed a database of genome sequences of 650 people who gave consent before they died for their DNA genomes to be researched. The scientists also had access to cellular RNA in up to 40 tissue samples. 

“A lot of human genomicists have overlooked these integrated HHV-6 sequences in human genomes. They’re not in the human reference sequences and they’re not common enough to rise on the radar,” Greninger said. The researchers identified six individuals who had HHV-6 integrated in their genomes: two with HHV-6A and four with HHV-6B. The RNA sequences revealed that in these individuals, a number of viral genes were being actively expressed, in particular one gene called U90 and another called U100. In most tissues, the level of expression was low and sporadic, but the highest expressions were found in the esophagus, testes, adrenal gland and brain. The gene U100 codes for a viral protein that is part of the viral outer shell, or envelope. U90 codes for a protein known as a transactivator, which means it promotes the expression of other genes....

Published in Journal of Virology (Open Access)(Oct. 9, 2019)

https://doi.org/10.1128/JVI.01418-19