Human Herpesvirus-6A and -6B (HHV-6A and HHV-6B): The Role of Roseoloviruses in Neurological Dysfunction and the Mechanisms of Viral-Induced Epileptogenesis.

Human herpesvirus-6 consists of a pair of viral species, HHV-6A and HHV-6B, which are neurotropic with the ability to invade, persist, and reactivate within the nervous system. Accumulating evidence links HHV-6 to epilepsy and other neuropathologies, including: multiple sclerosis, chronic fatigue syndrome, and neurodegeneration. Yet, mechanisms by which these viruses induce neurological disorders, including their role in epileptogenesis, remain unknown. It has been demonstrated that HHV-6 exhibits tropism for astrocytes, oligodendrocytes, and neurons. Thus, HHV-6 can perturb cellular homeostasis, neuronal signaling, and immune regulation, astrocytic glutamate clearance, GABAergic inhibition, and cholinergic or monoaminergic neurotransmission yielding network hyperexcitability. It is also reported that HHV-6 can activate neuroinflammation through Toll-Like Receptor (TLR), cytokine, and/or NF-κB activation, which facilitates neuronal injury and network instability. Indeed, a suite of converging processes suggest a multifactorial nature for HHV-6 related neuropathology. Despite robust experimental and clinical data, definitive causal relationships between HHV-6 and epilepsy (or induction of neurodegeneration) remain elusive. This review discusses evidence for roseolovirus-induced neurological dysfunction and disorders commonly associated with HHV-6A and HHV-6B infections. A preponderance of clinical and experimental evidence suggests that differential tropism for distinct neuronal neurotransmitter chemotypes and glia as well as systemic effects are involved in roseolovirus-mediated neurological disease.