Kooperativer Bibliotheksverbund

Berlin Brandenburg

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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 06 August 2013, Vol.110(32), pp.13126-31
    Description: Human CMV (hCMV) establishes lifelong infections in most of us, causing developmental defects in human embryos and life-threatening disease in immunocompromised individuals. During productive infection, the viral 〉230,000-bp dsDNA genome is expressed widely and in a temporal cascade. The hCMV genome does not carry histones when encapsidated but has been proposed to form nucleosomes after release into the host cell nucleus. Here, we present hCMV genome-wide nucleosome occupancy and nascent transcript maps during infection of permissive human primary cells. We show that nucleosomes occupy nuclear viral DNA in a nonrandom and highly predictable fashion. At early times of infection, nucleosomes associate with the hCMV genome largely according to their intrinsic DNA sequence preferences, indicating that initial nucleosome formation is genetically encoded in the virus. However, as infection proceeds to the late phase, nucleosomes redistribute extensively to establish patterns mostly determined by nongenetic factors. We propose that these factors include key regulators of viral gene expression encoded at the hCMV major immediate-early (IE) locus. Indeed, mutant virus genomes deficient for IE1 expression exhibit globally increased nucleosome loads and reduced nucleosome dynamics compared with WT genomes. The temporal nucleosome occupancy differences between IE1-deficient and WT viruses correlate inversely with changes in the pattern of viral nascent and total transcript accumulation. These results provide a framework of spatial and temporal nucleosome organization across the genome of a major human pathogen and suggest that an hCMV major IE protein governs overall viral chromatin structure and function.
    Keywords: Chip-Chip ; Epigenetic Regulation ; Functional Genomics ; Herpesvirus ; Chromatin -- Genetics ; Cytomegalovirus -- Genetics ; Genome, Viral -- Genetics ; Immediate-Early Proteins -- Genetics ; Nucleosomes -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 07 March 2006, Vol.103(10), pp.3840-5
    Description: Type I IFNs are crucial components of the innate immune response to viral attack. They are rapidly synthesized and secreted after infection with human cytomegalovirus (CMV) and trigger a signal transduction pathway that involves successive activation and nuclear translocation of signal transducer and activator of transcription 1 (STAT1) and STAT2. The activated STATs, together with the IFN regulatory factor 9 protein, form a trimeric transcription complex (IFN-stimulated gene factor 3) that stimulates expression of numerous IFN-responsive genes, many of which exhibit antiviral activity. Here we demonstrate that the viral 72-kDa IE1 protein (IE1-72kDa) confers partial resistance to the antiviral activity of type I IFNs upon CMV. Accordingly, IFN-responsive transcripts accumulate to substantially increased levels after infection with an IE1-deficient mutant as compared with wild-type virus, and ectopic expression of the viral protein in stably transfected cells is sufficient to block their induction. We further show that IE1-72kDa forms a physical complex with STAT1 and STAT2 in nuclei of infected cells and in vitro and prevents association of STAT1, STAT2, and IFN regulatory factor 9 with promoters of IFN-responsive genes in vivo. Our results indicate that the viral protein blocks an intranuclear step after nuclear translocation and before DNA binding of IFN-stimulated gene factor 3, presumably by interfering with the integrity and/or correct subnuclear localization of the protein complex. This study identifies the CMV IE1-72kDa protein as a viral antagonist of the cellular innate immune response, inhibiting IFN-dependent STAT signaling by means of an unprecedented molecular mechanism.
    Keywords: Cytomegalovirus -- Immunology ; Interferon Type I -- Metabolism ; Stat1 Transcription Factor -- Metabolism ; Stat2 Transcription Factor -- Metabolism
    ISSN: 0027-8424
    E-ISSN: 10916490
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  • 3
    Language: English
    In: Cellular and Molecular Life Sciences, 2011, Vol.68(6), pp.1079-1090
    Description: Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised individuals. Here, non-toxic concentrations of the anti-cancer kinase inhibitor sorafenib were shown to inhibit replication of different HCMV strains (including a ganciclovir-resistant strain) in different cell types. In contrast to established anti-HCMV drugs, sorafenib inhibited HCMV major immediate early promoter activity and HCMV immediate early antigen (IEA) expression. Sorafenib is known to inhibit Raf. Comparison of sorafenib with the MEK inhibitor U0126 suggested that sorafenib inhibits HCMV IEA expression through inhibition of Raf but independently of signaling through the Raf downstream kinase MEK 1/2. In concordance, siRNA-mediated depletion of Raf but not of MEK-reduced IEA expression. In conclusion, sorafenib diminished HCMV replication in clinically relevant concentrations and inhibited HCMV IEA expression, a pathophysiologically relevant event that is not affected by established anti-HCMV drugs. Moreover, we demonstrated for the first time that Raf activation is involved in HCMV IEA expression.
    Keywords: Human cytomegalovirus ; Sorafenib ; Kinase inhibitor ; Raf ; Immediate early antigen ; Cancer chemotherapy ; Oncomodulation ; Antiviral therapy
    ISSN: 1420-682X
    E-ISSN: 1420-9071
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  • 4
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 07 December 2004, Vol.101(49), pp.17234-9
    Description: The human cytomegalovirus 72-kDa immediate-early (IE)1 and 86-kDa IE2 proteins are expressed at the start of infection, and they are believed to exert much of their function through promiscuous transcriptional activation of viral and cellular gene expression. Here, we show that the impaired growth of an IE1-deficient mutant virus in human fibroblasts is efficiently rescued by histone deacetylase (HDAC) inhibitors of three distinct chemical classes. In the absence of IE1 expression, the viral major IE and UL44 early promoters exhibited decreased de novo acetylation of histone H4 during the early phase of infection, and the hypoacetylation correlated with reduced transcription and accumulation of the respective gene products. Consistent with these findings, IE1 interacts specifically with HDAC3 within infected cells. We also demonstrate an interaction between IE2 and HDAC3. We propose that the ability to modify chromatin is fundamental to transcriptional activation by IE1 and, likely, IE2 as well.
    Keywords: Histone Deacetylase Inhibitors ; Virus Replication ; Immediate-Early Proteins -- Physiology ; Viral Proteins -- Physiology
    ISSN: 0027-8424
    E-ISSN: 10916490
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  • 5
    Language: English
    In: PLoS Pathogens, April, 2011, Vol.7(4)
    Description: Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. in addition, persistent hCMV infection may contribute to various chronic disease conditions even in immunologically normal people. The pathogenesis of hCMV disease has been frequently linked to inflammatory host immune responses triggered by virus-infected cells. Moreover, hCMV infection activates numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the relative contributions of individual viral gene products to these changes in cellular transcription. We systematically analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major transcriptional activator and antagonist of type I interferon (IFN) signaling, on the human transcriptome. Following expression under conditions closely mimicking the situation during productive infection, iE1 elicits a global type II IFN-like host cell response. This response is dominated by the selective up-regulation of immune stimulatory genes normally controlled by IFN-[gamma] and includes the synthesis and secretion of pro-inflammatory chemokines. IE1- mediated induction of IFN-stimulated genes strictly depends on tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1) and correlates with the nuclear accumulation and sequence-specific binding of STAT1 to IFN- [gamma]-responsive promoters. However, neither synthesis nor secretion of IFN-[gamma] or other IFNs seems to be required for the IE1- dependent effects on cellular gene expression. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host transcriptional response via an unexpected STAT1-dependent but IFN-independent mechanism and identify IE1 as a candidate determinant of hCMV pathogenicity.
    Keywords: Cytomegalovirus -- Health Aspects ; Cytomegalovirus -- Research ; Interferon -- Physiological Aspects ; Interferon -- Research ; Stat1 -- Physiological Aspects ; Stat1 -- Research ; Viral Proteins -- Physiological Aspects ; Viral Proteins -- Research
    ISSN: 1553-7366
    Source: Cengage Learning, Inc.
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  • 6
    Language: English
    In: PLoS Pathogens, 2011, Vol.7(4), p.e1002016
    Description: Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. In addition, persistent hCMV infection may contribute to various chronic disease conditions even in immunologically normal people. The pathogenesis of hCMV disease has been frequently linked to inflammatory host immune responses triggered by virus-infected cells. Moreover, hCMV infection activates numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the relative contributions of individual viral gene products to these changes in cellular transcription. We systematically analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major transcriptional activator and antagonist of type I interferon (IFN) signaling, on the human transcriptome. Following expression under conditions closely mimicking the situation during productive infection, IE1 elicits a global type II IFN-like host cell response. This response is dominated by the selective up-regulation of immune stimulatory genes normally controlled by IFN-γ and includes the synthesis and secretion of pro-inflammatory chemokines. IE1-mediated induction of IFN-stimulated genes strictly depends on tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1) and correlates with the nuclear accumulation and sequence-specific binding of STAT1 to IFN-γ-responsive promoters. However, neither synthesis nor secretion of IFN-γ or other IFNs seems to be required for the IE1-dependent effects on cellular gene expression. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host transcriptional response via an unexpected STAT1-dependent but IFN-independent mechanism and identify IE1 as a candidate determinant of hCMV pathogenicity. ; Human cytomegalovirus (hCMV) is a leading cause of birth defects and severe disease in people with compromised immunity. Disease caused by hCMV is frequently linked to inflammation, and the virus has been shown to induce numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the contributions of individual viral proteins to these changes in cellular transcription. We systematically analyzed the effects of the hCMV immediate-early 1 (IE1) protein, a major viral transcriptional activator, on expression of 〉28,000 human genes. Following expression under conditions mimicking the situation during hCMV infection, IE1 elicited a transcriptional response dominated by the up-regulation of pro-inflammatory and immune stimulatory genes normally induced by the secreted signaling protein interferon-γ. However, IE1-mediated gene expression was independent of interferon induction, yet required the activated form of signal transducer and activator of transcription 1 (STAT1), a central mediator of interferon signaling. Indeed, STAT1 moved to the nucleus and became associated with IE1 target genes upon expression of the viral protein. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host cell response via an unexpected mechanism and suggest that IE1 may contribute to hCMV disease in more direct ways than previously thought.
    Keywords: Research Article ; Biology ; Medicine ; Genetics And Genomics ; Immunology ; Virology ; Infectious Diseases ; Microbiology ; Molecular Biology ; Computational Biology
    ISSN: 1553-7366
    E-ISSN: 1553-7374
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  • 7
    In: The Journal of Virology, 2008, Vol. 82(22), p.11167
    Description: The genomes of herpesviruses, including human cytomegalovirus (CMV), are double-stranded DNA molecules maintained as episomes during infection. The viral DNA lacks histones when encapsidated in the virion. However, it has been found histone associated inside infected cells, implying unidentified chromatin assembly mechanisms. Our results indicate that components of the host cell nucleosome deposition machinery target intranuclear CMV DNA, resulting in stepwise viral-chromatin assembly. CMV genomes undergo limited histone association and nucleosome assembly as early as 30 min after infection via DNA replication-independent mechanisms. Low average viral-genome chromatinization is maintained throughout the early stages of infection. The late phase of infection is characterized by a striking increase in average histone occupancy coupled with the process of viral-DNA replication. While the initial chromatinization affected all analyzed parts of the CMV chromosome, a subset of viral genomic regions, including the major immediate-early promoter, proved to be largely resistant to replication-dependent histone deposition. Finally, our results predict the likely requirement for an unanticipated chromatin disassembly process that enables packaging of histone-free DNA into progeny capsids.
    Keywords: Chromatin Assembly and Disassembly ; Cytomegalovirus -- Physiology ; DNA, Viral -- Metabolism ; Histones -- Metabolism;
    ISSN: 0022-538X
    ISSN: 0022538X
    E-ISSN: 10985514
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  • 8
    Language: English
    In: Reviews in medical virology, May 2011, Vol.21(3), pp.154-80
    Description: Herpesvirus infections of humans can cause a broad variety of symptoms ranging from mild afflictions to life-threatening disease. During infection, the large double-stranded DNA genomes of all herpesviruses are transcribed, replicated and encapsidated in the host cell nucleus, where DNA is typically structured and manoeuvred through nucleosomes. Nucleosomes individually assemble DNA around core histone octamers to form 'beads-on-a-string' chromatin fibres. Herpesviruses have responded to the advantages and challenges of chromatin formation in biologically unique ways. Although herpesvirus DNA is devoid of histones within nucleocapsids, nuclear viral genomes most likely form irregularly arranged or unstable nucleosomes during productive infection, and regular nucleosomal arrays resembling host cell chromatin in latently infected cells. Besides variations in nucleosome density, herpesvirus chromatin 'bead strings' undergo dynamic changes in histone composition and modification during the different stages of productive replication, latent infection and reactivation from latency, raising the likely possibility that epigenetic processes may dictate, at least in part, the outcome of infection and ensuing pathogenesis. Here, we summarise and discuss several new and important aspects regarding the nucleosome-based mechanisms that regulate herpesvirus chromatin structure and function in infected cells. Special emphasis is given to processes of histone deposition, histone variant exchange and covalent histone modification in relation to the transcription from the viral genome during productive and latent infections by human cytomegalovirus and herpes simplex virus type 1. We also present an overview on emerging histone-directed antiviral strategies that may be developed into 'epigenetic therapies' to improve current prevention and treatment options targeting herpesvirus infection and disease.
    Keywords: Virus Replication ; Chromatin -- Metabolism ; Cytomegalovirus -- Physiology ; DNA, Viral -- Metabolism ; Herpesvirus 1, Human -- Physiology ; Histones -- Metabolism ; Nucleosomes -- Metabolism
    E-ISSN: 1099-1654
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  • 9
    Language: English
    In: Medical microbiology and immunology, June 2015, Vol.204(3), pp.285-93
    Description: The morphogenesis of human cytomegalovirus (HCMV) particles is incompletely understood. Analysis of the protein composition of HCMV virions and subviral dense bodies (DBs) by mass spectrometry provides valuable information to increase our knowledge about viral morphogenesis. Here we addressed the viral proteome of virions and DBs from two fibroblast-passaged isolates and the widely used endotheliotropic TB4-BAC40 strain of HCMV. The results show a striking concordance of the particle proteomes of different strains. One surprising finding was that only low levels of gpUL128-131A were found in TB40-BAC4 virions. These three proteins, together with gH and gL, form a protein complex that is critical for the endothelial cell tropism of that strain. This indicates that either few molecules of that complex per virion or a small fraction of pentamer-positive virions suffice to retain the tropism. Furthermore, using a pp65-deficient variant of TB40-BAC4, we confirm our previous finding that the major tegument protein serves as a scaffold to support the upload of a fraction of the outer tegument proteins into particles. The results demonstrate that HCMV particle morphogenesis is an orchestrated process that leads to the formation of particles with a largely strain-independent protein composition.
    Keywords: Proteome ; Proteomics ; Virion ; Cytomegalovirus -- Classification ; Viral Proteins -- Metabolism
    ISSN: 03008584
    E-ISSN: 1432-1831
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  • 10
    Language: English
    In: Journal of virology, September 2012, Vol.86(18), pp.9817-27
    Description: In the nuclei of permissive cells, human cytomegalovirus genomes form nucleosomal structures initially resembling heterochromatin but gradually switching to a euchromatin-like state. This switch is characterized by a decrease in histone H3 K9 methylation and a marked increase in H3 tail acetylation and H3 K4 methylation across the viral genome. We used ganciclovir and a mutant virus encoding a reversibly destabilized DNA polymerase to examine the impact of DNA replication on histone modification dynamics at the viral chromatin. The changes in H3 tail acetylation and H3 K9 methylation proceeded in a DNA replication-independent fashion. In contrast, the increase in H3 K4 methylation proved to depend widely on viral DNA synthesis. Consistently, labeling of nascent DNA using "click chemistry" revealed preferential incorporation of methylated H3 K4 into viral (but not cellular) chromatin during or following DNA replication. This study demonstrates largely selective epigenetic tagging of postreplicative human cytomegalovirus chromatin.
    Keywords: Chromatin -- Genetics ; Cytomegalovirus -- Genetics ; Histones -- Metabolism
    ISSN: 0022538X
    E-ISSN: 1098-5514
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