Detection of human herpesvirus-6 in mesial temporal lobe epilepsy surgical brain resections

Donati, D.; Akhyani, Nahid; Fogdell‐Hahn, Anna; Cermelli, Claudio; Cassiani-Ingoni, Riccardo; Vortmeyer, Alexander O.; Heiss, John D.; Cogen, P H; Gaillard, William D.; Satô, Susumu; Theodore, William H.; Jacobson, Steven

doi:10.1212/01.wnl.0000094357.10782.f9

Cited by 184 publications

(208 citation statements)

References 46 publications

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“…Arguments against this hypothesis have been suggested by a recent report demonstrating the presence of active HHV-6 infection in the absence of inflammation in brain samples from a subset of patients with mesial temporal lobe epilepsy (14). Importantly, this study demonstrated the presence of HHV-6-infected astrocytes, supporting the assumption that resident glial cells and not only peripheral lymphocytes leaking through the blood brain barrier might harbor the virus.…”

supporting

confidence: 75%

“…The primers and probes used (Applied Biosystems, Foster City, CA) were specific for the immediate-early region of variants A and B (25). Samples were also quantitatively titrated for human genomic ␤-actin DNA on a third real-time PCR assay, and final viral DNA load per 10 6 cells was calculated by the following formula: (HHV-6 DNA copy number/␤-actin DNA copy number/2) ϫ 10 6 ϭ HHV-6 DNA copy number/ 10 6 cells (14). Results were plotted and sorted using the Sequence Detector System program (Perkin-Elmer, Wellesley, MA).…”

Section: Methodsmentioning

confidence: 99%

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Variant-Specific Tropism of Human Herpesvirus 6 in Human Astrocytes

Donati

Martinelli

Cassiani-Ingoni

et al. 2005

J Virol

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Though first described as a lymphotropic virus, human herpesvirus 6 (HHV-6) is highly neuropathogenic. Two viral variants are known: HHV-6A and HHV-6B. Both variants can infect glial cells and have been differentially associated with central nervous system diseases, suggesting an HHV-6 variant-specific tropism for glial cell subtypes. We have performed infections with both viral variants in human progenitor-derived astrocytes (HPDA) and monitored infected cell cultures for cytopathic effect (CPE), intra-and extracellular viral DNA load, the presence of viral particles by electronic microscopy, mRNA transcription, and viral protein expression. HHV-6A established a productive infection with CPE, visible intracellular virions, and high virus DNA loads. HHV-6B-infected HPDA showed no morphological changes, intracellular viral particles, and decreasing intra-and extracellular viral DNA over time. After long-term passage, HHV-6B-infected HPDA had stable but low levels of intracellular viral DNA load with no detectable viral mRNA. Our results demonstrate that HHV-6A and HHV-6B have differential tropisms and patterns of infection for HPDA in vitro, where HHV-6A results in a productive lytic infection. In contrast, HHV-6B was associated with a nonproductive infection. These findings suggest that HHV-6 variants might be responsible for specific infection patterns in glial cells in vivo. Astrocytes may be an important reservoir for this virus in which differential tropism of HHV-6A and HHV-6B may be associated with different disease outcomes.

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supporting

confidence: 75%

Section: Methodsmentioning

confidence: 99%

Variant-Specific Tropism of Human Herpesvirus 6 in Human Astrocytes

Donati

Martinelli

Cassiani-Ingoni

et al. 2005

J Virol

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“…Typically, CNS infections by HHV-6 lead to benign viral latency, a strategy for persistence used by all members of the herpesvirus family. HHV-6 has been recently demonstrated to infect primary human oligodendrocytes in vitro and in vivo (Albright et al, 1998;Mock et al, 1999;Blumberg et al, 2000;Goodman et al, 2003), as well as human astrocytes (He et al, 1996;Donati et al, 2003), but virtually nothing is known about its effects on glial precursor cells, from which both oligodendrocytes and astrocytes originate.…”

Section: Introductionmentioning

confidence: 99%

Infection with an Endemic Human Herpesvirus Disrupts Critical Glial Precursor Cell Properties

Dietrich¹,

Blumberg²,

Roshal³

et al. 2004

J. Neurosci.

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Human herpesvirus 6 (HHV-6), a common resident virus of the human CNS, has been implicated in both acute and chronic inflammatory-demyelinating diseases. Although HHV-6 persists within the human CNS and has been described to infect mature oligodendrocytes, nothing is known about the susceptibility of glial precursors, the ancestors of myelin-producing oligodendrocytes, to viral infection.We show that HHV-6 infects human glial precursor cells in vitro. Active infection was demonstrated by both electron microscopy and expression of viral gene transcripts and proteins, with subsequent formation of cell syncytia. Infection leads to alterations in cell morphology and impairment of cell replication but not increased cell death. Infected cells showed decreased proliferation as measured by bromodeoxyuridine uptake, which was confirmed by blunting of the cell growth rate of infected cells compared with uninfected controls over time. The detailed analysis using novel, fluorescent-labeled HHV-6A or HHV-6B reagents demonstrated strong G 1 /S phase inhibition in infected precursor cells. Cell cycle arrest in HHV-6-infected cells was associated with a profound decrease in the expression of the glial progenitor cell marker A2B5 and a corresponding increase in the oligodendrocyte differentiation marker GalC.These data demonstrate for the first time that infection of primary human glial precursor cells with a neurologically relevant human herpesvirus causes profound alterations of critical precursor cell properties. In light of recent observations that repair of CNS demyelination is dependent on the generation of mature oligodendrocytes from the glial precursor cell pool, these findings may have broad implications for both the ineffective repair seen in demyelinating diseases and the disruption of normal glial maturation.

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“…Several PCR studies of tissue removed during temporal lobectomy from patients with mesial temporal lobe epilepsy have examined the potential etiologic role of HHV6 (47)(48)(49)(50)(51)(52). Results have been variable (Table 2).…”

Section: Human Herpes Virus 6bmentioning

confidence: 99%

Epilepsy and Viral Infections

Theodore

2014

Epilepsy Curr

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Detection of human herpesvirus-6 in mesial temporal lobe epilepsy surgical brain resections

Cited by 184 publications

References 46 publications

Variant-Specific Tropism of Human Herpesvirus 6 in Human Astrocytes

Variant-Specific Tropism of Human Herpesvirus 6 in Human Astrocytes

Infection with an Endemic Human Herpesvirus Disrupts Critical Glial Precursor Cell Properties

Epilepsy and Viral Infections

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