Herpes simplex virus-infected cell protein 0 blocks the silencing of viral DNA by dissociating histone deacetylases from the CoREST-REST complex

A preeminent phenotype of the infected cell protein 0 (ICP0) of herpes simplex virus 1 (HSV-1) is that it acts as a promiscuous transactivator. In most cell lines exposed to ΔICP0 mutant virus at low ratios of virus per cell infection, α genes are expressed but the transition to β and γ gene expression does not ensue, but can be enhanced by inhibitors of histone deacetylases (HDACs). Earlier studies have shown that ICP0 interacts with CoREST and displaces HDAC1 from the CoREST-REST-HDAC1/2 complex. HDAC1 and CoREST are then independently translocated to the cytoplasm. Here, we test the hypothesis that ICP0 blocks the silencing of HSV DNA by displacing HDAC1 from the CoREST-REST complex. Specifically, first, mapping studies led us to construct a truncated CoREST (CoREST_146-482) that in transfected cells displaced HDAC1 from the CoREST-REST complex. Second, we constructed two viruses. In BACs encoding the entire HSV-1, we replaced the gene encoding ICP0 with AmpR to yield a ΔICP0 mutant R8501. We also replaced ICP0 with CoREST_146-482 to yield recombinant R8502. The yield of R8502 mutant virus in Vero, HEp-2, and human embryonic lung cells exposed to 0.1 pfu of virus per cell was 100-, 10-, and 10-fold higher, respectively, than those of R8501 mutant virus. In Vero cells, the yield of R8502 was identical with that of wild-type virus. We conclude that CoREST_146-482 functionally replaced ICP0 and that, by extension, ICP0 acts to block the silencing of viral DNA by displacing HDAC1/2 from the CoREST-REST complex.