Models for human cytomegalovirus (HCMV) brain infection have been developed in a variety of brain-derived cells in which the factors governing virus infectivity might be studied in vitro. Studies were initiated with brain endothelial cells, the likely portal of entry for virus into the central nervous system. Primary explant cultures of brain endothelial cells, derived from homogenates of healthy human brain, supported complete viral gene expression and cytopathic effect (CPE). Endothelial cells do not appear to be a barrier for HCMV passage into the central nervous system. Astroglial lines (primary explant or tumor-derived) varied in their ability to support HCMV replication. Some (T98G) supported incomplete (immediate-early) gene expression while others (A-172) did not support any detectable gene expression. Some astroglial lines (HS-683) supported extensive virus replication with minimal viral CPE. Neuronal cell lines (SK-N-MC) were fully permissive. The more differentiated glial lines (astrocytoma) were fully permissive to HCMV infection; however, the less differentiated glial lines (glioblastoma) were partly or nonpermissive.
To study fetal brain infection with human cytomegalovirus (HCMV), an in vitro model was established using the human primary nontransformed neuronal cell line HCN-1A. On exposure to a mixture of factors promoting differentiation, HCN-1A cells differentiate into mature neurons. Both undifferentiated and differentiated neurons were permissive to HCMV replication as assessed by immunohistochemistry and in situ DNA hybridization. Infectious center assays revealed that the ratio of virus-infected differentiated cells to undifferentiated cells dropped from 11:1 to 2:1 7-21 days after infection. However, release of infectious progeny from the differentiated HCN-1A cells was greater by 100- to 1000-fold. Cytopathic effect appeared earlier and was more pronounced in differentiated cells. These results suggest that differentiation of HCN-1A cells dramatically affects the rate and amount of virus production from these cells. This model should be useful in the study of congenital HCMV disease and virus-host cell interaction.
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