Histone Modifications Associated with Latent HSV1 Genomes

Modification of histone tails influences chromatin structure and might regulate transcription by affecting chromatin configuration (Jenuwein and Allis 2001; Egger et al. 2004). Acetylated histones mark transcriptionally active domains of chromatin while histone deacetylation is associated with silencing of promoter activity.

Arthur et al. used a neonatal rat dorsal root ganglion-derived neuronal culture system to study HSV-1 latency and reactivation in vitro. They constructed recombinant viruses carrying reporter genes under the control of viral promoters and observed that, in latently infected cultures, inhibition of histone deacetylases by trichostatin A (TSA) switched on the activity of HSV-1 IE110 promoter (Arthur et al. 2001). They speculated that this could be an indirect effect mimicking nerve growth factor (NGF) withdrawal (which also switches on the lytic cycle) because TSA can induce expression of certain cellular factors blocking NGF action (Sano and Kitayama 1996).

Kubat et al., using the same in vivo model system as in their DNA methyl-ation analysis, determined the level of histone H3 acetylation (at lysines 9 and 14) using a chromatin immunoprecipitation assay, at a region located within the LAT promoter, a region corresponding to the HSV-1 DNA polymerase gene (expressed in the early phase of the lytic cycle) and promoters of two IE genes (UL54/ICP27 promoter and ICP4 promoter). They found that the LAT promoter is enriched with acetyl histone H3 (K9, K14) compared to the viral polymerase gene and the IE promoters analyzed. They speculated that in latently infected, terminally differentiated, quiescent neurons, HSV-1 employs a relatively dynamic epigenetic mechanism—i.e., histone acetylation and deacetylation—to activate the LAT promoter and repress lytic viral promoters, respectively (Kubat et al. 2004a). In a follow-up study, they observed that the LAT enhancer (including rcr, a region critical for induced reactivation of HSV-1) is hyperacetylated even in the absence of LAT transcription and suggested that this cis-acting regulator region maintains a transcriptionally permissive chromatin domain (Kubat et al. 2004b).

Histone deacetylation might explain the highly efficient silencing of heterologous promoters incorporated into recombinant HSV-1 genomes that occurs after establishment of the latent state (a phenomenon observed by Lo-kensgard et al. 1994). The mouse phosphoglycerate kinase (PGK) promoter is highly active and the murine metallothionein promoter (MT1) shows a moderate activity after acute (productive) infection of dorsal root ganglia by the recombinant viruses; they do not drive, however, the expression of the lacZ reporter gene in the latent phase of infection (Lokensgard et al. 1994).

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