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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    • "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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    ABSTRACT: In this autopsy-based study, human herpesvirus-6 (HHV-6) and -7 (HHV-7) genomic sequence frequency, HHV-6 variants, HHV-6 load and the expression of HHV-6 antigens in brain samples from the individuals, with and without unspecified encephalopathy (controls), using nested and real-time polymerase chain reactions, restriction endonuclease, and immunohistochemical analysis were examined. GraphPad Prism 6.0 Mann-Whitney nonparametric and chi-square test and Fisher's exact test were used for statistical analysis. The encephalopathy diagnoses were shown by magnetic resonance imaging made during their lifetime and macro- and microscopically studied autopsy tissue materials. Widespread HHV-6 and/or HHV-7 positivity was detected in the brain tissue of various individuals with encephalopathy, as well as in controls (51/57, 89.4 % and 35/51, 68.6 %, respectively; p = 0.009). Significantly higher detection frequency of single HHV-6 and concurrent HHV-6 + HHV-7 DNA was found in pia mater meninges, frontal lobe, temporal lobe, and olfactory tract DNAs in individuals with encephalopathy compared to the control group. HHV-6 load and higher frequency of the viral load >10 copies/10(6) cells significantly differed in samples from individuals with and without encephalopathy. The expression of HHV-6 antigens was revealed in different neural cell types with strong predominance in the encephalopathy group. In all HHV-6-positive autopsy samples of individuals with and without encephalopathy, HHV-6B was revealed. Significantly higher detection frequency of beta-herpesvirus DNA, more often detected HHV-6 load >10 copies/10(6) cells, as well as the expression of HHV-6 antigens in different brain tissue samples from individuals with encephalopathy in comparison with control group indicate on potential involvement of these viruses in encephalopathy development.
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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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    ABSTRACT: Dynamic adjustments to neuronal energy supply in response to synaptic activity are critical for neuronal function. Glial cells known as astrocytes have processes that ensheath most central synapses and express G-protein-coupled neurotransmitter receptors and transporters that respond to neuronal activity. Astrocytes also release substrates for neuronal oxidative phosphorylation and have processes that terminate on the surface of brain arterioles and can influence vascular smooth muscle tone and local blood flow. Membrane receptor or transporter-mediated effects of glutamate represent a convergence point of astrocyte influence on neuronal bioenergetics. Astrocytic glutamate uptake drives glycolysis and subsequent shuttling of lactate from astrocytes to neurons for oxidative metabolism. Astrocytes also convert synaptically reclaimed glutamate to glutamine, which is returned to neurons for glutamate salvage or oxidation. Finally, astrocytes store brain energy currency in the form of glycogen, which can be mobilized to produce lactate for neuronal oxidative phosphorylation in response to glutamatergic neurotransmission. These mechanisms couple synaptically driven astrocytic responses to glutamate with release of energy substrates back to neurons to match demand with supply. In addition, astrocytes directly influence the tone of penetrating brain arterioles in response to glutamatergic neurotransmission, coordinating dynamic regulation of local blood flow. We will describe the role of astrocytes in neurometabolic and neurovascular coupling in detail and discuss, in turn, how astrocyte dysfunction may contribute to neuronal bioenergetic deficit and neurodegeneration. Understanding the role of astrocytes as a hub for neurometabolic and neurovascular coupling mechanisms is a critical underpinning for therapeutic development in a broad range of neurodegenerative disorders characterized by chronic generalized brain ischemia and brain microvascular dysfunction.
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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.
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