Human Herpesvirus 6 Genome and Antigen in Acute Multiple Sclerosis Lesions

Goodman, Andrew; Mock, David J.; Powers, James M.; Baker, Jeffrey V.; Blumberg, Benjamin M.

doi:10.1086/368172

Cited by 115 publications

(88 citation statements)

References 54 publications

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“…HHV-6 has also been detected, albeit at low levels, in Hodgkin's lymphoma and angioimmunoblastic lymphadenopathy, 42 and has been implicated in multiple sclerosis. 43 HHV-6 infection is common in early childhood, when it presents as a febrile illness with rash, known as roseola. In healthy adults, HHV-6 DNA has been detected in saliva and salivary gland epithelium.…”

Section: Discussionmentioning

confidence: 99%

Anatomical mapping of human herpesvirus reservoirs of infection

Chen

Hudnall

2006

Modern Pathology

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Section: Discussionmentioning

confidence: 99%

Anatomical mapping of human herpesvirus reservoirs of infection

Chen

Hudnall

2006

Modern Pathology

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“…In disease in which HHV-6A has been implicated (34), this viral variant could reach the CNS via infected inflammatory cells. The hallmark of the MS lesion is inflammation in which both oligodendrocytes (17) and astrocytes have been shown to contain HHV-6 (7,27). Direct viral infection of these cells may be associated with abundant expression of viral antigens and might contribute to an immune-mediated response against viral antigens or shared sequence or conformational homology with self-proteins (molecular mimicry).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies on autopsy brain samples from patients with MS have reported a higher frequency of HHV-6 DNA in MS plaques as opposed to normal-appearing white matter of the same patients and to unaffected brain specimens (7,17), and a recent investigation has documented significantly higher levels of HHV-6 gene transcripts in both lesional and normal-appearing white matter in autopsy brain samples from MS patients than in those from normal controls (27).…”

mentioning

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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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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“…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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Human Herpesvirus 6 Genome and Antigen in Acute Multiple Sclerosis Lesions

Cited by 115 publications

References 54 publications

Anatomical mapping of human herpesvirus reservoirs of infection

Anatomical mapping of human herpesvirus reservoirs of infection

Variant-Specific Tropism of Human Herpesvirus 6 in Human Astrocytes

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

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