Increased Replication of Human Cytomegalovirus in Retinal Pigment Epithelial Cells by Valproic Acid Depends on Histone Deacetylase Inhibition

Michaelis, Martin; Suhan, Tatyana; Reinisch, Alexander; Reisenauer, Agnes; Fleckenstein, Corinna; Eikel, Daniel; Gümbel, H.; Nau, Heinz; Cinatl, Jindrich

doi:10.1167/iovs.05-0369

Cited by 34 publications

(28 citation statements)

References 38 publications

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“…However, much data suggests that viral lytic gene expression may be repressed initially upon infection, which becomes particularly evident in studies at lower m.o.i. For instance, histone deacetylase inhibition increases the efficiency of both MCMV and HCMV infection (KuntzSimon & Obert, 1995;Michaelis et al, 2005;Tang & Maul, 2003). Similarly, others have shown that cellular factors associated with ND10, e.g.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…A recent study has suggested that initially, upon infection, viral IE promoters become associated with an active chromatin configuration, whereas early and late promoters become associated with repressive chromatin and, as infection proceeds, dynamic changes in the chromatin structure of these early and late gene promoters occurs (Cuevas-Bennett & Shenk, 2008). However, evidence from studies using murine CMV (MCMV) have shown that addition of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) to permissive cells increases the levels of murine IE1 gene expression (Tang & Maul, 2003) and, tellingly, others have shown that treatment of human fibroblast or epithelial cells with the pan-specific HDAC inhibitor valproic acid also increases viral IE late gene expression (Kuntz-Simon & Obert, 1995;Michaelis et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Lytic infection of permissive cells with human cytomegalovirus is regulated by an intrinsic ‘pre-immediate-early’ repression of viral gene expression mediated by histone post-translational modification

Groves

Reeves

Sinclair

2009

Journal of General Virology

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Human cytomegalovirus (HCMV) lytic gene expression occurs in a regulated cascade, initiated by expression of the viral major immediate-early (IE) proteins. Transcribed from the major IE promoter (MIEP), the major IE genes regulate viral early and late gene expression. This study found that a substantial proportion of infecting viral genomes became associated with histones immediately upon infection of permissive fibroblasts at low m.o.i. and these histones bore markers of repressed chromatin. As infection progressed, however, the viral MIEP became associated with histone marks, which correlate with the known transcriptional activity of the MIEP at IE time points. Interestingly, this chromatin-mediated repression of the MIEP at 'pre-IE' times of infection could be overcome by inhibition of histone deacetylases, as well as by infection at high m.o.i., and resulted in a temporal advance of the infection cycle by inducing premature viral early and late gene expression and DNA replication. As well as the MIEP, and consistent with previous observations, the viral early and late promoters were also initially associated with repressive chromatin. However, changes in histone modifications around these promoters also occurred as infection progressed, and this correlated with the known temporal regulation of the viral early and late gene expression cascade. These data argue that the chromatin structure of all classes of viral genes are initially repressed on infection of permissive cells and that the chromatin structure of HCMV gene promoters plays an important role in regulating the time course of viral gene expression during lytic infection. INTRODUCTIONHuman cytomegalovirus (HCMV) productively infects numerous cell types in the human host (Fish et al., 1998;Hertel et al., 2003;Lathey & Spector, 1991;Riegler et al., 2000;Sinzger et al., 1995), as well as establishing a latent infection in bone marrow myeloid progenitor cells (Kondo et al., 1994;Mendelson et al., 1996;Sindre et al., 1996). Whether the outcome of infection is lytic or latent is dependent on whether robust viral immediate-early (IE) gene expression occurs, producing viral gene products crucial for the subsequent expression of early and late genes (Meier & Stinski, 1996;Spector, 1996;Wathen & Stinski, 1982). A number of studies have informed the general consensus that, in undifferentiated cell types, such as undifferentiated myeloid cells, transcription from the major IE promoter (MIEP) is repressed by differentiation-dependent transcriptional repressors and co-repressors, which impart on the MIEP an overall repressive chromatin structure. In contrast, differentiation of myeloid cells alters the balance of MIEP-specific repressors and activators, resulting in a chromatin structure around the MIEP conducive to transcription (Dosa et al., 2005;Ioudinkova et al., 2006;Murphy et al., 2002). These differentiation-dependent changes in the post-translational modifications of the histones around the MIEP are likely to be involved in the control of latency and reacti...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lytic infection of permissive cells with human cytomegalovirus is regulated by an intrinsic ‘pre-immediate-early’ repression of viral gene expression mediated by histone post-translational modification

Groves

Reeves

Sinclair

2009

Journal of General Virology

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“…on May 12, 2018 by guest http://jvi.asm.org/ alone or in the presence of another HDAC inhibitor which activates HCMV gene expression, VPA (46,59,60), and determined the percentage of IE1-positive nuclei. As expected, there were essentially no IE1-positive cells in undifferentiated monocytes.…”

Section: Vol 81 2007 Hcmv Uses Daxx Defense For Latent-like Infectimentioning

confidence: 99%

Human Cytomegalovirus Gene Expression Is Silenced by Daxx-Mediated Intrinsic Immune Defense in Model Latent Infections Established In Vitro

Saffert

Kalejta

2007

J Virol

130

211

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In addition to productive lytic infections, herpesviruses such as human cytomegalovirus (HCMV) establish a reservoir of latently infected cells that permit lifelong colonization of the host. When latency is established, the viral immediate-early (IE) genes that initiate the lytic replication cycle are not expressed. HCMV IE gene expression at the start of a lytic infection is facilitated by the viral pp71 protein, which is delivered to cells by infectious viral particles. pp71 neutralizes the Daxx-mediated cellular intrinsic immune defense that silences IE gene expression by generating a repressive chromatin structure on the viral major IE promoter (MIEP). In naturally latently infected cells and in cells latently infected in vitro, the MIEP also adopts a similar silenced chromatin structure. Here we analyze the role of Daxx in quiescent HCMV infections in vitro that mimic some, but not all, of the characteristics of natural latency. We show that in these "latent-like" infections, the Daxx-mediated defense that represses viral gene expression is not disabled because pp71 and Daxx localize to different cellular compartments. We demonstrate that Daxx is required to establish quiescent HCMV infections in vitro because in cells that would normally foster the establishment of these latent-like infections, the loss of Daxx causes the lytic replication cycle to be initiated. Importantly, the lytic cycle is inefficiently completed, which results in an abortive infection. Our work demonstrates that, in certain cell types, HCMV must silence its own gene expression to establish quiescence and prevent abortive infection and that the virus usurps a Daxx-mediated cellular intrinsic immune defense mechanism to do so. This identifies Daxx as one of the likely multiple viral and cellular determinants in the pathway of HCMV quiescence in vitro, and perhaps in natural latent infections as well.

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“…HDAC1 and -2 always exist together and are found in three different complexes (Sin3, NuRD/NRD/Mi2, and CoREST) (20). HDACs have been found to be associated with several herpesviruses, such as cytomegalovirus (CMV) and herpes simplex type 1 (HSV-1), interacting with viral promoters or viral proteins and negatively affecting their gene expression, leading to subsequent reduction in viral replication (22)(23)(24)(25). Several…”

mentioning

confidence: 99%

Leucine Zipper Domain Is Required for Kaposi Sarcoma-associated Herpesvirus (KSHV) K-bZIP Protein to Interact with Histone Deacetylase and Is Important for KSHV Replication

Martinez

Tang

2012

Journal of Biological Chemistry

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Increased Replication of Human Cytomegalovirus in Retinal Pigment Epithelial Cells by Valproic Acid Depends on Histone Deacetylase Inhibition

Abstract: The data demonstrate that VPA stimulates HCMV replication by HDAC inhibition independent of Erk 1/2 phosphorylation in therapeutic concentrations in RPE cells. Therefore, patients at risk of HCMV retinitis who are treated with VPA or other HDAC inhibitors should be carefully monitored.

Cited by 34 publications

References 38 publications

Lytic infection of permissive cells with human cytomegalovirus is regulated by an intrinsic ‘pre-immediate-early’ repression of viral gene expression mediated by histone post-translational modification

Lytic infection of permissive cells with human cytomegalovirus is regulated by an intrinsic ‘pre-immediate-early’ repression of viral gene expression mediated by histone post-translational modification

Human Cytomegalovirus Gene Expression Is Silenced by Daxx-Mediated Intrinsic Immune Defense in Model Latent Infections Established In Vitro

Leucine Zipper Domain Is Required for Kaposi Sarcoma-associated Herpesvirus (KSHV) K-bZIP Protein to Interact with Histone Deacetylase and Is Important for KSHV Replication

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