Human Cytomegalovirus Latency is Associated with the State of Differentiation of the Host Cells: an in vitro Model in Teratocarcinoma Cells

The human cytomegalovirus (HCMV) major immediate-early (MIE) gene is not transcribed in undifferentiated NTera-2 embryonal carcinoma cells, but is transcribed in their differentiated derivatives, offering a model with which to study the developmental regulation of the activity of a viral gene during the differentiation of these cells. The molecular mechanisms involved in the blockade of the MIE gene expression in undifferentiated NTera2 cells include covalent closure of the circular conformation of the viral genome, silencing of the viral MIE promoter by histone deacetylation, and increases in the expression of negatively regulating transcription factors responsible for the recruitment of the histone deacytylases around the viral MIE promoter (MIEP), resulting in repression of the MIEP in undifferentiated cells. The treatment of NTera2 cells with retinoic acid induces the differentiation of these cells. In HCMV-infected differentiated NTera2 cells, the MIEP becomes associated with hyperacetylated histones, which results in an open structure of chromatin, enhancing the access of DNA- binding factors which positively regulate MIE gene expression and viral replication. This model system contributes to an understanding of HCMV latency and reactivation in vivo in the cells of the myeloid lineage