Human Herpesvirus 6 and Neuroinflammation

Human herpesvirus (HHV-) 6A and HHV-6B are two distinct β-herpesviruses which have been associated with various neurological diseases, including encephalitis, meningitis, epilepsy, and multiple sclerosis. Although the reactivation of both viruses is recognized as the cause of some neurological complications in conditions of immunosuppression, their involvement in neuroinflammatory diseases in immunocompetent people is still unclear, and the mechanisms involved have not been completely elucidated. Here, we review the available data providing evidence for the capacity of HHV-6A and -6B to infect the central nervous system and to induce proinflammatory responses by infected cells. We discuss the potential role of both viruses in neuroinflammatory pathologies and the mechanisms which could explain virus-induced neuropathogenesis. 1. Introduction Human herpesvirus (HHV-) 6 was first isolated in 1986 by Salahuddin and colleagues [1]. This enveloped DNA virus belongs to the β-herpesvirus family and, together with its closest homologue HHV-7, forms the roseoloviruses subfamily. HHV-6 is widely spread in the population (seroprevalence > 90%) and can establish a persistent and most often asymptomatic infection in humans. Based on genetic, epidemiological, and functional features, the numerous isolated strains of HHV-6 were initially separated into two variants, HHV-6A and HHV-6B, which have recently been recognized as two distinct viruses. HHV-6A and -6B share an overall sequence identity of 90%, and several open reading frames are present in only one of the two viruses [2]. Primary infection with HHV-6B generally happens before the age of two; the virus is transmitted through saliva and close contacts with parents [3] and provokes exanthem subitum (or roseola), a benign febrile illness with skin rash. HHV-6A infection is thought to happen later in life and was not yet clearly identified as the causative agent for any disease. To date, the only identified cellular receptor for both HHV-6A and -6B is the complement-regulatory transmembrane protein CD46 [4]. This protein is ubiquitously expressed in humans, allowing the viruses to infect a wide range of cells and tissues, including cells from the central nervous system (CNS). Both viruses have a high tropism towards T cells, which are the best virus producers in vitro, and can establish a persistent infection in different tissues, including the salivary glands (for HHV-6B only) and peripheral lymphocytes. In immunocompromised patients, HHV-6A and -6B often reactivate and can provoke neurological pathologies.