... The long latency between childhood febrile seizures and the appearance of persistent unprovoked seizures suggests these patients may have chronic HHV-6 infection rather than reactivated virus. The presence of chronic viral infection in these patients would be supported by the progression of hippocampal atrophy. Collectively, these data suggest an ongoing process; the latency between occurrence of an early risk factor such as febrile seizures and onset of chronic epilepsy is consistent with either persistent or reactivated infection [25,32].
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An association between chronic epilepsy and persistent or reactivated HHV-6 infection of astrocytes suggests the possibility that viral infection of astrocytes are associated with changes in cell function that may contribute to disease. Astrocytes are known to interact closely with neurons and are critical in modulating synaptic transmission [49]. Astrocytes can modulate neurotransmission by maintaining low concentrations of extracellular glutamate by the glial glutamate transporters EAAT-1 and EAAT-2 [50]. Elevated extracellular glutamate, the main excitatory neurotransmitter, may be involved in epilepsy by triggering excitotoxicity through loss of glutamine synthetase [51], an enzyme that metabolizes glutamate in astrocytes, and/or by malfunctioning astrocytic glutamate transporters [50]. The CA1 and CA3 neurons lost in MTS/MTLE are particularly susceptible to glutamatergic-mediated cell death. Sclerotic hippocampi from temporal lobe epilepsy demonstrate reduced EAAT-2 immunoreactivity [52], and are prone to alternative EAAT-2 mRNA splicing [53]. A unique finding in this study is the isolation ex vivo of cultured astrocytes from patients with MTLE who are infected with HHV-6. These primary HHV-6–infected astrocytes demonstrated low levels of EAAT-2 mRNA. In support of our ex vivo findings, astrocytes infected with HHV-6 in vitro also demonstrated a remarkable decrease in EAAT-2 mRNA. Detection of high levels of HHV-6 DNA in MTLE brain tissue, isolation of HHV-6 from primary astrocytes isolated from MTLE brain tissue, and decreased expression of EAAT-2 mRNA demonstrates an association between HHV-6 infection and astrocytic dysfunction. Functional changes in virus infected glia or in glia harboring reactivated virus may lead to secondary injury of the exquisitely sensitive hippocampal neuron, and ultimately to development of MTLE and epilepsy. The potential relationship between HHV-6 astrocytic infection and MTLE deserves further investigation.
