Herpesviruses in Neurodegenerative Disease and Dementia

Viruses have long been investigated for their possible associations with a multitude of neurodegenerative diseases. Recently, herpesviruses, such as human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV), have been of growing interest as potential triggers or contributors in the pathogenesis of Alzheimer’s disease (AD) and other causes of dementia. The role that herpesviruses play in these disease processes remains unclear, with evidence for the infectious hypothesis of AD often ambiguous and strongly debated. Obtaining definitive evidence for the role of herpesviruses in AD and other dementia-related diseases remains challenging due to many factors, including the complexities of multifactorial diseases, the unique lifecycle of herpesviruses, and the lack of translational in vivo models of herpesvirus infection and AD. We investigated the potential association of herpesviruses with these diseases through the application of bioinformatic analyses and molecular techniques to human whole genome sequences (WGS) and the utilization of a nonhuman primate model, the common marmoset (Callithrix jacchus).

We observed a higher prevalence of HHV-6 partial integration in synucleinopathies associated with dementia compared to other cohorts. We characterized Callitrichine herpesvirus 3 (CalHV-3) in the common marmoset as a translational model of gammaherpesvirus infection, highlighting similarities to human EBV infection. We described beta-amyloid (Ab) pathology in the brains of herpesvirus infected and uninfected marmosets. In marmosets infected with CalHV-3, we noted lower plasma Ab42:40 ratios and GFAP levels and a positive correlation between viral load and Ab42, Ab40, and total tau. These findings suggest that herpesviruses may play a role in dementia-related neurodegenerative diseases through multiple different mechanisms, including the integration of viral genomes and the alteration or augmentation of disease biomarkers.