The Presence of Human Herpesvirus 6 in the Brain in Health and Disease

The human herpesvirus 6 (HHV-6) -A and -B are two dsDNA beta-herpesviruses infecting almost the entire worldwide population. These viruses have been implicated in multiple neurological conditions in individuals of various ages and immunological status, including encephalitis, epilepsy, and febrile seizures. HHV-6s have also been suggested as playing a role in the etiology of neurodegenerative diseases such as multiple sclerosis and Alzheimer’s disease. The apparent robustness of these suggested associations is contingent on the accuracy of HHV-6 detection in the nervous system. The effort of more than three decades of researching HHV-6 in the brain has yielded numerous observations, albeit using variable technical approaches in terms of tissue preservation, detection techniques, sample sizes, brain regions, and comorbidities. In this review, we aimed to summarize current knowledge about the entry routes and direct presence of HHV-6 in the brain parenchyma at the level of DNA, RNA, proteins, and specific cell types, in healthy subjects and in those with neurological conditions. We also discuss recent findings related to the presence of HHV-6 in the brains of patients with Alzheimer’s disease in light of available evidence.