Herpes Simplex Virus ICP0 Promotes both Histone Removal and Acetylation on Viral DNA during Lytic Infection

  • Cliffe A
  • Knipe D
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Abstract

During lytic infection, the genome of herpes simplex virus 1 (HSV-1) is associated with limited levels of histones but does not form a regular repeating nucleosomal structure. However, the previous observation that chromatin remodeling factors are recruited into viral replication compartments indicates that chromatin remodeling plays a role in HSV-1 gene expression and DNA replication. In this study we demonstrate the presence of histone H3 on HSV-1 DNA early in infection at levels equivalent to those found on a cellular gene. The proportion of viral DNA associated with histone H3 decreases at later times postinfection, independently of either viral DNA replication or transcription. We demonstrate that an immediate-early protein, infected cell protein 0 (ICP0), is required for both a reduction in the proportion of HSV-1 DNA associating with histone H3 and an increase in histone acetylation. This study provides evidence that ICP0 directly alters the chromatin structure of the HSV-1 genome during lytic infection, and this system will serve as a useful model for the reduction of histone load in higher eukaryotes. Eukaryotic DNA is packaged into a protein-DNA complex known as chromatin. The basic structure of chromatin is the nucleosome, which consists of core histone proteins (H2A, H2B, H3, and H4) around which 147 bp of DNA is wrapped. Modification of the chromatin structure to allow access to proteins involved in DNA replication, recombination and re-pair, and gene expression is a key mechanism utilized by the cell to regulate these processes. Chromatin structure can be modified by covalent modification of histones and DNA, as well as noncovalent chromatin remodeling. Chromatin remod-eling, carried out by ATPase-dependent chromatin remodeling complexes, results in the sliding of nucleosomes along the DNA, unwinding of nucleosomes, and/or complete removal of nucleosomes (65). Histone acetylation is one of the best-char-acterized covalent histone modifications and is a hallmark of transcriptionally active chromatin. Histone acetylation is thought to result in relaxation of the basic chromatin structure through both increased charge repulsion (20) and by serving as a binding site for chromatin-remodeling complexes (1, 29, 38). Like cellular DNA, the genomes of DNA viruses that rep-licate within the nucleus also associate with chromatin, albeit to varied degrees (48). The genome of herpes simplex virus 1 (HSV-1) has been shown to associate with histones during both lytic infection of epithelial cells and latent infection of neurons (13, 32, 39). During latent infection, the viral genome is pack-aged into nucleosomes and forms a classical laddering pattern following digestion with micrococcal nuclease (13). Consistent with the silencing of lytic genes during a latent infection, lytic gene promoters show markers of heterochromatin, such as H3K9me2, and low levels of histone acetylation (43, 78). In contrast, during lytic infection, regular repeating nucleosome arrays of HSV-1 DNA have not been detected (39, 45, 47). However, at least a portion of the viral DNA associates with histones (32, 39), although one study showed that histone as-sociation with immediate-early (IE) gene promoters was low in the presence of functional VP16 (32). A recent study by Oh and Fraser reported that the HSV-1 genome associated with histones at early times postinfection and the proportion of viral DNA associating with histones decreased at late times in the infectious cycle. The authors attributed this decrease to an increase in newly synthesized genomes that were free of his-tones (55). The histones present on viral DNA during lytic infection show modifications associated with active gene expression, namely, acetylation of histone H3 and di-and trimethylation of histone H3 lysine 4 (32, 36, 39). Given that regulation of chromatin structure has important consequences for DNA processes, it is likely that both viral and cellular gene products manipulate the HSV-1 chromatin structure to allow gene ex-pression and DNA replication to take place. Consistent with this, proteins involved in both chromatin remodeling and his-tone modifications are recruited into viral replication compart-ments (75), which are the sites of late gene transcription and DNA replication (3, 9, 10, 41, 57, 62). The activation domain of the HSV-1 VP16 virion transacti-vator has been shown to interact with ATPase-dependent chro-matin remodeling proteins and histone acetyltransferases (54, 76). Deletion of the VP16 activation domain results in a de-crease in recruitment of ATPase-dependent chromatin remod-eling proteins and histone acetyltransferases to IE promoters and an accompanying increase in histone occupancy and de-crease in histone acetylation (32). An additional candidate for modifying chromatin on the HSV-1 genome is the immediate-early protein ICP0. ICP0 is able to stimulate the expression of all three classes of viral genes in infected cells (4, 7) and cotransfected genes (14, 21, 53, 56, 61), although it does not bind DNA directly (17). The ability of ICP0 null viruses to replicate in tissue culture cells is dependent upon both the cell

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Authors

  • A. R. Cliffe

  • D. M. Knipe

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