Central nervous system infection of the human herpesvirus-6 and mechanisms of neuroinflammation mediated by engagement of the CD46 virus receptor

Infectious etiology in multiple sclerosis (MS) has previously been raised. Despite many studies demonstrating associations with multiple pathogens, no MS-specific agent has been identified. Thus, it has been hypothesized that in genetically susceptible individuals, infectious agents could act as triggers in eliciting aberrant immune responses directed against the central nervous system (CNS). The human herpesvirus-6 (HHV-6), a neurotropic virus, is a frequently implicated candidate pathogens in MS. To better understand the role of HHV-6 in the pathogenesis of neurologic diseases, we compared detection of cell-free HHV-6 DNA and antibody reactivity in the cerebrospinal fluid (CSF) specimens of various neurologic cohorts. Differences in levels of HHV-6 antibody and HHV-6 DNA expression in various neurologic cohorts were demonstrated. To understand the specific mechanisms that allow HHV-6 infection of the CNS, whether HHV-6 could infect primary human astrocyte cultures in vitro and explored the potential of this virus to enter the CNS using the olfactory pathway by infecting a specialized group of glial cells located in the nasal cavity known as olfactory ensheathing glial cells (OEGCs) was investigated. The findings suggest ability of HHV-6 to enter and establish life-long residency in the brain through infection of glial cells such as OEGCs and CNS astrocytes. Furthermore, we hypothesize that immune surveillance may actively be involved in preventing CNS activation of HHV-6 in healthy individuals. Impairment in immune control, however, could lead to viral reactivations. Using paired CSF and sera specimen of a small cohort patients who were treated with natalizumab, a monoclonal antibody against the alpha-4-beta-integrin molecule used in treatment of MS that blocks immune cell trafficking to the brain, we demonstrated evidence of HHV-6 reactivation by PCR detection, suggesting reduction in circulating immune cells is associated with viral reactivation within the CNS. Moreover, binding of the HHV-6 with the CD46 virus receptor/T cell co-stimulatory molecule was also investigated as a possible mechanism contributing to a by-stander pro-inflammatory reaction associated with neural tissue damage in genetically susceptible individuals.