Article

Association of Human Herpesvirus-6B with Mesial Temporal Lobe Epilepsy

Università degli Studi di Siena, Siena, Tuscany, Italy
PLoS Medicine (Impact Factor: 14.43). 06/2007; 4(5):e180. DOI: 10.1371/journal.pmed.0040180
Source: PubMed

ABSTRACT

Human herpesvirus-6 (HHV-6) is a beta-herpesvirus with 90% seroprevalence that infects and establishes latency in the central nervous system. Two HHV-6 variants are known: HHV-6A and HHV-6B. Active infection or reactivation of HHV-6 in the brain is associated with neurological disorders, including epilepsy, encephalitis, and multiple sclerosis. In a preliminary study, we found HHV-6B DNA in resected brain tissue from patients with mesial temporal lobe epilepsy (MTLE) and have localized viral antigen to glial fibrillary acidic protein (GFAP)-positive glia in the same brain sections. We sought, first, to determine the extent of HHV-6 infection in brain material resected from MTLE and non-MTLE patients; and second, to establish in vitro primary astrocyte cultures from freshly resected brain material and determine expression of glutamate transporters.
HHV-6B infection in astrocytes and brain specimens was investigated in resected brain material from MTLE and non-MTLE patients using PCR and immunofluorescence. HHV-6B viral DNA was detected by TaqMan PCR in brain resections from 11 of 16 (69%) additional patients with MTLE and from zero of seven (0%) additional patients without MTLE. All brain regions that tested positive by HHV-6B variant-specific TaqMan PCR were positive for viral DNA by nested PCR. Primary astrocytes were isolated and cultured from seven epilepsy brain resections and astrocyte purity was defined by GFAP reactivity. HHV-6 gp116/54/64 antigen was detected in primary cultured GFAP-positive astrocytes from resected tissue that was HHV-6 DNA positive-the first demonstration of an ex vivo HHV-6-infected astrocyte culture isolated from HHV-6-positive brain material. Previous work has shown that MTLE is related to glutamate transporter dysfunction. We infected astrocyte cultures in vitro with HHV-6 and found a marked decrease in glutamate transporter EAAT-2 expression.
Overall, we have now detected HHV-6B in 15 of 24 patients with mesial temporal sclerosis/MTLE, in contrast to zero of 14 with other syndromes. Our results suggest a potential etiology and pathogenic mechanism for MTLE.

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    • "At the same time, the presence of HHV-6 DNA, viral mRNA, and late viral antigen gp116/54/64 expressions in astrocytes in brain samples from patients with multiple sclerosis (MS) (Goodman et al. 2003), mesial temporal lobe epilepsy (MTLE) (Donati et al. 2003;Fotheringham et al. 2007b;Theodore et al. 2008;Kawamura et al. 2015;Esposito et al. 2015), nervous tissue tumors (Cuomo et al. 2001), and in hippocampal astrocytes of recipients after bone marrow transplantation (Fotheringham et al. 2007a) has been shown, which may represent active viral infection. HHV-6 has been associated with neurologic pathologies such as MS (Ablashi et al. 2000;Chapenko et al. 2003;Opsahl and Kennedy 2005;Behzad-Behbabani et al. 2011;NoraKrukle et al. 2011) and encephalitis, which are associated with inflammation, MTLE in the absence of inflammation in brain tissue (Donati et al. 2003;Fotheringham et al. 2007b;Niehusmann et al. 2010), myalgic encephalomyelitis/chronic fatigue syndrome (Ablashi et al. 2000;Chapenko et al. 2006Chapenko et al. , 2012aBansal et al. 2012), and with different neurological complications after allogeneic hematopoietic stem cell transplantation (Fujimaki et al. 2006;Wang et al. 2006;Scheurer et al. 2013;Bhanushali et al. 2013) and solid organ transplantations (Chapenko et al. 2009;Massih and Razonable 2009). Although a significant number of studies have suggested that the CNS can be a site for persistent HHV-6 and HHV-7 infection, the role of these viruses in the human CNS disease and encephalopathy, as well as ways for viruses to enter into the CNS, remains to be defined. "
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    • "The origins of this disorder are not completely understood (McCormick and Contreras, 2001; Scharfman, 2007), but neuronal hyperexcitability is believed to be caused by disequilibrium between glutamatergic and GABAergic neurotransmission , either by decreased inhibitory (GABA) circuits or excessive glutamatergic release (Dudek et al., 1999; Uhlhaas and Singer, 2006). Dysfunctional astrocyte glutamate-glutamine cycling is also involved (Tian et al., 2005), as astrocyte expression of EAAT2 is diminished in epilepsy patients (Proper et al., 2002; Fotheringham et al., 2007), and knock-down of glutamate transporters [EAAC1 (Sepkuty et al., 2002), GLT-1 (Tanaka et al., 1997), and GLAST (Watase et al., 1998)] in animal models exacerbates neuronal excitability. Also, glutamine synthetase expression is reduced by 40% in astrocytes of epilepsy patients, suggesting that glutamate degradation is greatly diminished (Eid et al., 2004). "
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    • "The virus reactivates later in life, and might lead to severe and sometimes fatal disease in immune compromised individuals [9]. Moreover, HHV-6B infection has been associated with various diseases, including mesial temporal lope epilepsy [10]. "
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