Integrated retroviral
DNA is subject to epigenetic transcriptional silencing at different frequencies. This process is mediated by repressive DNA methylation and histone modifications on viral
chromatin. However, the detailed mechanisms by which retroviral silencing is initiated and maintained are not well understood. Using a model system in which avian sarcoma virus (ASV)
DNA is epigenetically repressed in mammalian cells, we previously found that a cellular scaffolding
protein, Daxx, acts as an antiretroviral factor that promotes epigenetic repression through recruitment of
histone deacetylases (HDACs). Here we show that
human Daxx protein levels are increased in response to retroviral
infection and that Daxx acts at the time of
infection to initiate epigenetic repression. Consistent with a rapid and active
antiviral epigenetic response, we found that repressive histone marks and long terminal repeat (LTR) DNA methylation could be detected within 12 h to 3 days postinfection, respectively. Daxx was also found to be required for long-term ASV silencing maintenance and full
viral DNA methylation, and it was physically associated with both
viral DNA and
DNA methyltransferases (DNMTs). These findings support a model in which incoming retroviral
protein-
DNA complexes are detected by Daxx, and the integrated provirus is rapidly chromatinized and repressed by DNA methylation and
histone modification as part of an
antiviral response. These results uncover a possible direct and active
antiviral mechanism by which DNMTs can be recruited to retroviral
DNA.