Virus World

Researchers at Baylor College of Medicine report today in the journal Neuron evidence that refutes the link between increased levels of herpes virus and Alzheimer's disease. In addition, the researchers provide a new statistical and computational framework for the analysis of large-scale sequencing data. About 50 million people worldwide are affected by Alzheimer's disease, a type of progressive dementia that results in the loss of memory, cognitive abilities and verbal skills, and the numbers are growing rapidly. Currently available medications temporarily ease the symptoms or slow the rate of decline, which maximizes the time patients can live and function independently. However, there are no treatments to halt progression of Alzheimer's disease.

"Like all types of dementia, Alzheimer's disease is characterized by massive death of brain cells, the neurons. Identifying the reason why neurons begin and continue to die in the brains of Alzheimer's disease patients is an active area of research," said corresponding author Dr. Zhandong Liu, associate professor of pediatrics at Baylor and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital. One theory that has gained traction in the past year is that certain microbial infections, such as those caused by viruses, can trigger Alzheimer's disease. A 2018 study reported increased levels of human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) in the postmortem brain tissues of more than 1,000 patients with Alzheimer's disease when compared to the brain tissues of healthy-aging subjects or those suffering from a different neurodegenerative condition. Presence of elevated levels of genetic material of herpes viruses indicated active infections, which were linked to Alzheimer's disease. In less than a year, this study generated a flurry of excitement and led to the initiation of several studies to better understand the link between viral infections and Alzheimer's disease. 

Surprisingly, when co-author Dr. Hyun-Hwan Jeong, a postdoctoral fellow in Dr. Liu's group and others, reanalyzed the data sets from the 2018 study using the identical statistical methods with rigorous filtering, as well as four commonly used statistical tools, they were unable to produce the same results. The team was motivated to reanalyze the data from the previous study because they observed that while the p-values (a statistical parameter that predicts the probability of obtaining the observed results of a test, assuming that other conditions are correct) were highly significant, they were being ascribed to data in which the differences were not visually appreciable. Moreover, the p-values did not fit with simple logistic regression—a statistical analysis that predicts the outcome of the data as one of two defined states. In fact, after several types of rigorous statistical tests, they found no link between the abundance of herpes viral DNA or RNA and likelihood of Alzheimer's disease in this cohort...

Published in Neuron (December 18, 2019):

https://doi.org/10.1016/j.neuron.2019.11.009

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

Researchers link the Human Herpes Virus 6A to the development of multiple sclerosis. Researchers at Karolinska Institutet have developed a new method to separate between two different types of a common herpes virus (HHV-6) that has been linked to multiple sclerosis. By analyzing antibodies in the blood against the most divergent proteins of herpesvirus 6A and 6B, the researchers were able to show that MS-patients carry the herpesvirus 6A to a greater extent than healthy individuals. The findings, published in Frontiers in Immunology, point to a role for HHV-6A in the development of MS. 

Multiple sclerosis, MS, is an autoimmune disease that affects the central nervous system. The cause of the disease is unclear, but one plausible explanation is a virus tricks the immune system to attack the body's own tissue. Human Herpesvirus 6 (HHV-6) has previously been associated with MS, but in those studies it wasn't possible to distinguish between 6A and 6B. Through virus isolation from ill individuals, researchers have been able to show that HHV-6B can cause mild conditions such as roseola in children, but it has been unclear if HHV-6A is the cause of any disease. According to estimates, as many as 80 percent of all children are infected with the HHV-6 virus before 2 years of age, and many also carry protection in the form of antibodies against this particular virus for the rest of their lives. But since it hasn't been possible to tell the two variants apart post-infection, it has been difficult to say whether HHV-6A or B is a risk factor for MS. In this study, however, the researchers were able to distinguish between the A and B virus by analyzing antibodies in the blood against the proteins--immediate early protein 1A and 1B (IE1A and IE1B)--that diverge the most between the two viruses.

The researchers compared antibody levels in blood samples of some 8,700 MS-patients against more than 7,200 healthy people whose gender, date of birth, date of blood sample and other factors matched those with MS. They concluded that people with MS had a 55 percent higher risk of carrying antibodies against the HHV-6A protein than the control group. In a sub-group of almost 500 people, whose blood samples were drawn before the onset of the disease, the risk of developing MS in the future was more than doubled if they had a 6A viral infection. The younger the people were when the virus was first discovered in the blood, the higher the risk was of developing MS in the future. HHV-6B, on the other hand, was not positively associated with MS. Instead MS-patients had lower levels of antibodies toward IE1B than those without MS. 

Antibodies toward Epstein-Barr virus (EBV), another herpes virus that is also associated with MS, were analyzed with the same method and the researchers were able to show that individuals affected with both viruses had an even greater risk of MS. This indicates that several virus infections could be acting jointly to increase the risk of MS. "Both HHV-6A and 6B can infect our braincells, but they do it in slightly different ways. Therefore, it is now interesting to go forward and attempt to map out exactly how the viruses could affect the onset of MS," says Anna Fogdell-Hahn.

Published in Frontiers  in Immunology (26 November 2019):

https://doi.org/10.3389/fimmu.2019.02715

A new finding that even took the study’s authors by surprise lends support to the controversial idea that microbes play a role in Alzheimer’s disease. The research published June 21 in Neuron, found convincing signs that certain types of herpes virus may promote the complex process that leads to the disease that afflicts some 5.7 million Americans. The study points to the viruses as possible accomplices that drive disease progression but does not suggest that Alzheimer’s may begin after they are transmitted through casual contact. 

Joel Dudley, a geneticist and genomic scientist at the Icahn School of Medicine at Mount Sinai and senior author of the new paper, had not intended to investigate this theory when his lab began working on the newly published study in 2013. The plan he had made with colleagues was to identify possible new Alzheimer’s drug targets by looking at the molecular changes in the brain that occur during the disease. Thanks to a new NIH-led public-private partnership called the Accelerating Medicines Partnership Alzheimer's Disease (AMP-AD), the team had access to data from 876 brains—some healthy and some with early- or late-stage Alzheimer’s. They used DNA and RNA sequencing to parse out genetic differences between the groups as well as differences in how inherited genes were expressed or made into RNA. That’s when they started getting strange results. “The algorithms kept returning this pattern for viral biology,” Dudley says.

The team found more viral DNA in Alzheimer’s brains compared with healthy brains—specifically, high levels of DNA from human herpesvirus 6A (HHV-6A). RNA of both HHV-6A and HHV-7 were also higher in the Alzheimer’s brains than in healthy brains, and viral RNA levels tracked with the severity of clinical symptoms. HHV-6A is a usually symptom-less virus that infects people later in life. HHV-7 infects more than 80 percent of infants, often causing a rash.

Original research Published in Neuron on June 21, 2018

https://doi.org/10.1016/j.neuron.2018.05.023