Infection with an endemic human herpesvirus disrupts critical glial precursor cell properties.

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 G1/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.

Human herpesvirus 6 genome and antigen in acute multiple sclerosis lesions.

Evidence for a candidate multiple sclerosis (MS) virus, human herpesvirus 6 (HHV-6), was sought in biopsy specimens of acute lesions that presented clinically as cerebral tumors obtained from 5 patients. Histopathology, magnetic resonance imaging, and clinical course confirmed the diagnosis of MS in each case. A sensitive in situ polymerase chain reaction (ISPCR) method was used to detect HHV-6 genome, in conjunction with immunocytochemical staining (ICC) to detect viral and cellular antigens. ISPCR revealed numerous oligodendrocytes, lymphocytes, and microglia containing HHV-6 genome within all lesions, whereas ICC showed only the HHV-6 glycoprotein 116 antigen in some reactive astrocytes and microglia. High frequencies of neuroglial and inflammatory cells containing HHV-6 genome were present in acute-phase lesion tissue from patients who were free of the effects of chronic MS and had not been received immunomodulatory therapy for MS. The prevalence of HHV-6 genome-containing cells, including oligodendrocytes, in each lesion suggests that HHV-6 plays a role in the demyelinative pathogenesis of MS; the significance of the discrepant expression of viral antigens remains uncertain.