Chromatin-mediated epigenetic regulation of HSV-1 transcription as a potential target in antiviral therapy

Abstract

The ability to establish, and reactivate from, latent infections is central to the biology and pathogenesis of HSV-1. It also poses a strong challenge to antiviral therapy, as latent HSV-1 genomes do not replicate or express any protein to be targeted. Although the processes regulating the establishment and maintenance of, and reactivation from, latency are not fully elucidated, the current general consensus is that epigenetics play a major role. A unifying model postulates that whereas HSV-1 avoids or counteracts chromatin silencing in lytic infections, it becomes silenced during latency, silencing which is somewhat disrupted during reactivation. Many years of work by different groups using a variety of approaches have also shown that the lytic HSV-1 chromatin is distinct and has unique biophysical properties not shared with most cellular chromatin. Nonetheless, the lytic and latent viral chromatins are typically enriched in post translational modifications or histone variants characteristic of active or repressed transcription, respectively. Moreover, a variety of small molecule epigenetic modulators inhibit viral replication and reactivation from latency. Despite these successes in culture and animal models, it is not obvious how epigenetic modulation would be used in antiviral therapy if the same epigenetic mechanisms governed viral and cellular gene expression. Recent work has highlighted several important differences between the viral and cellular chromatins, which appear to be of consequence to their respective epigenetic regulations. In this review, we will discuss the distinctiveness of the viral chromatin, and explore whether it is regulated by mechanisms unique enough to be exploited in antiviral therapy.

Keywords: Antiviral; Chromatin dynamics; Epigenetics; HSV-1; Herpes; Latency.

Fig. 1.

Epigenetic chromatin regulation. Top, silenced chromatin inaccessible to transcription factors and some of its typical epigenetic modifications; Bottom, active chromatin accessible to transcription factors with some of its typical epigenetic modifications. Selected chromatin modifiers regulating the transitions between the two are presented at the sides of the arrows. Blue, DNA; orange, core nucleosome; green, linker histone H1 (darker shade for the least dynamic, lighter shade for the most dynamic); black oval, heterochromatin protein 1; gray oval, transcription factor TF; Gray rectangle, high mobility group proteins; dash arrows, disassembly and reassembly. Me/2/3, methylation, di- or tri-; Ac, acetylation; P, phosphorylation.

Fig. 2.

The HSV-1 lytic replication cycle. Yellow circles, nuclear HSV-1 genomes.

Fig. 3.

Typical structures of the promoters of HSV-1 IE, E and L genes. Cartoon on top, HSV-1 genome and ORF. Red, immediate early genes; Blue, early genes; Yellow, late genes; Gray rectangles and ovals, cognate sequences for the VP16/HCF-1/Oct1 complex or ICP4, which are recognized by viral proteins (alone or in complexes); Black rectangles, cognate sequences for cellular transcription factors. Green rectangles and ovals, TATA box or Inr elements. See the text for details and discussion.

Fig. 4.

The HSV-1 infection cycle in humans depicting lytic and latent infections; for details see the main text.

Fig. 5.

Chromatin protection assays. Left, protection of a regularly chromatinized DNA template and the expected DNA products. Right, protection of a dynamically chromatinized DNA template in which the residency time of the core nucleosome approaches that of the linker histones. Middle, resolution of the protected DNA fragments expected from each chromatin type. Blue, DNA; orange, core nucleosome; green, linker histone H1 (shades as in Fig. 1); Black arrows, cleavage sites; Blue rectangles, protected DNA fragments sizes, as resolved by agarose gel electrophoresis.

Fig. 6.

Roscovitine inhibits transcription driven by the ICP0 promoter in the HSV-1 genome but not by the same promoter recombined in the cellular genome. The ICP0 promoter (red line) recombined in cellular genome (blue line) remains accessible to transcription proteins in cells treated with roscovitine (top), whereas the same promoter (red line) in the viral genome (purple line) is inaccessible in the same cells (bottom). Blue line, cellular DNA; Purple line, viral DNA; light blue line, cellular promoters; red line, viral promoter.

Fig. 7.

Interactions between HSV-1 DNA, core histones, histone H3 or H4 with PTM associated with transcription or silencing, or CTCF. X-axis, HSV-1 genome; Y axes, number of publications describing any association with any given histone, PTM, or CTCF for that particular genome locus. Vertical lines, the regions of the HSV-1 genome analyzed, to scale (i.e., the coverage); Colors of lines (and triangle heads on top), type of infection analyzed (for CTCF), or region of the gene analyzed (promoter, TSS, gene, or LAT) for all others; Colors and sizes of circles on top of each line, histone or PTM analyzed or number of studies analyzing each particular association, respectively. H4ac, H4 acetylated in K5, K8, K12 or K16. Note that several of the loci evaluated are in the repeated regions.

Fig. 8.

Chromatin dynamics mediated regulation of cellular or viral transcription. Epigenetic regulation of a specific cellular gene with PTM characteristic of active transcription increases its accessibility to transcription proteins and therefore activates transcription, whereas another gene in the same chromosome remains tightly chromatinized with PTM characteristic of repression and transcriptionally inactive (top). Epigenetic regulation of HSV-1 genomes, in contrast, dictates the accessibility to entire genomes (bottom). HSV-1 genomes in dynamic and accessible chromatin, enriched in PTM associated with transcription, are accessible to transcription proteins and therefore transcriptionally competent although only the gene on top is actually transcribed at this time (left). HSV-1 genomes in less dynamic or accessible chromatin, enriched in PTM characteristic of silencing, are not accessible to transcription proteins and therefore the entire genomes are transcriptionally incompetent (right). Blue line, cellular DNA; Purple line, viral DNA; light blue line, cellular promoters; red line, viral promoters.