Risk factors for the chronic neurodegenerative condition known as Alzheimer’s disease (AD) include many cellular genes and pathogenic microbes. Nucleic acids of two ubiquitous human herpesviruses, HHV-6A and HHV-7, have been found at higher levels in AD brains compared with healthy controls, and appear to regulate genes implicated in risk of developing the disease.
The first results of a study designed to identify networks of genes that are involved in the etiology of AD implicated a role for viruses in the disease. RNA sequencing of affected brain regions from AD and healthy patients revealed genes associated with susceptibility to virus infection and antiviral responses. This finding prompted the authors to examine viral RNAs in AD and control brains. They found consistent increases of viral RNAs from two human herpesviruses, HHV-6A and HHV-7, in AD brains. These findings were corroborated with RNA sequencing data from three independent studies of post-mortem brain. Increased transcripts from either virus were not detected in samples from patients with other neurodegenerative diseases.
HHV-6A and HHV-7 are ubiquitous human herpesviruses that cause a rash known as exanthem subitum or roseola (pictured). Over 85% of adults have antibody to both viruses.
The finding of increased HHV-6A and HHV-7 in AD brains does not prove that these viruses caused the disease. Viral infection might have been promoted by the development of AD. To provide support for the hypothesis that viral infection causes AD, the authors sought a linkage between host genes, AD, and viral abundance. For example, they identified host genes that are associated with increased abundance of viral RNA; they encode proteins involved in innate immunity and antiviral sensing. Some of these genes have previously been identified as risk factors for AD. In other words, viral infection may turn on genes whose products then lead to AD. The results of these studies also reveal that other viruses impact the expression of AD risk genes, including a human adenovirus, HHV-8, and herpes simplex virus type 2.
A hallmark of AD is progressive neuronal dysfunction and death. The authors asked if viral and neuronal abundance might be correlated. They found for multiple viruses that increased viral RNAs was linked to decreased numbers of neurons, but only HHV-6A had this effect in multiple brain tissues.
The analysis revealed that the cellular microRNA miR-155, known to be an AD risk factor, is suppressed by HHV-6A infection. When the miR-155 gene was deleted from a mouse line that develops amyloidosis (a feature of AD), the brain plaques were larger and more numerous. If HHV-6A inhibits expression of miR-155, the targets of this microRNA might be de-repressed. In fact some of the genes that are up-regulated by HHV-6A in human brain are targets of miR-155. This microRNA could be a key mediator of neuronal loss and AD caused by virus infection.
Presence of HHV-6A in AD brain was also found to up-regulate networks of transcription factors that are involved in the expression of genes such as protein kinases that are associated with AD risk. A study of proteins produced in the AD brains allowed estimation of the consequences of viral RNA synthesis. The results indicate viral disruption of nucleotide pool metabolism, a known feature of AD.
This impressive study links increased viral RNAs in the AD brain with neuronal loss and genes involved in disease risk. However it does not prove that infection with HHV-6A or HHV-7 contributes to the onset or progression of AD. One way to establish a causal effect, according to the authors, would be to conduct a ‘prospective, intervention-based study’. Take a group of individuals with AD and treat one group with an antiviral such as ganciclovir or cidofovir to interfere with viral replication; the other group receives a placebo. Then wait and see if there is a difference in the progression of AD among the two groups.
The problem with such a prospective study is that most HHV-6 and HHV-7 infections occur in childhood: would it be too late to prevent or delay AD by treating years later? Meanwhile the gene networks identified in this study should provide many years of study to understand the interactions between viruses and genes involved in the development of AD.