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


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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    • "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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    Frontiers in Cellular Neuroscience 04/2013; 7:38. DOI:10.3389/fncel.2013.00038 · 4.29 Impact Factor
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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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    ABSTRACT: Infection with human herpesvirus (HHV)-6B alters cell cycle progression and stabilizes tumor suppressor protein p53. In this study, we have analyzed the activity of p53 after stimulation with p53-dependent and -independent DNA damaging agents during HHV-6B infection. Microarray analysis, Western blotting and confocal microscopy demonstrated that HHV-6B-infected cells were resistant to p53-dependent arrest and cell death after γ irradiation in both permissive and non-permissive cell lines. In contrast, HHV-6B-infected cells died normally through p53-independet DNA damage induced by UV radiation. Moreover, we identified a viral protein involved in inhibition of p53 during HHV-6B-infection. The protein product from the U19 ORF was able to inhibit p53-dependent signaling following γ irradiation in a manner similar to that observed during infection. Similar to HHV-6B infection, overexpression of U19 failed to rescue the cells from p53-independent death induced by UV radiation. Hence, infection with HHV-6B specifically blocks DNA damage-induced cell death associated with p53 without inhibiting the p53-independent cell death response. This block in p53 function can in part be ascribed to the activities of the viral U19 protein.
    PLoS ONE 03/2013; 8(3):e59223. DOI:10.1371/journal.pone.0059223 · 3.23 Impact Factor
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    • "There are two viral subtypes of HHV-6: type A and type B. HHV-6B is a common cause of both febrile illnesses and of FS (Hall et al., 1994; Caserta et al., 1998), whereas HHV-6A has been associated with reactivated infection later in life, predominantly in the central nervous system, often as a result of immunologic suppression (Dewhurst et al., 1993). HHV-7 primary infection is most often asymptomatic (Caserta et al., 1998), but like HHV-6, can present with fever and, in this setting, has an even higher association with FS (Caserta et al., 1998; Hall et al., 2006) Recent studies report evidence of HHV-6B in hippocampal specimens from surgical resections performed on adults with HS and medically refractory TLE, many of whom reported prolonged FS in childhood (Donati et al., 2003; Fotheringham et al., 2007; Provenzale et al., 2008). Together these studies suggest that HHV-6B may be a cause of FSE and in addition may contribute to hippocampal injury and subsequent TLE. "
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