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Berlin Brandenburg

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  • Replication
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  • 1
    Language: English
    In: Virology, 2004, Vol.330(1), pp.271-283
    Description: The human immunodeficiency virus type-1 (HIV-1) transframe domain p6* is located between the nucleocapsid protein (NC) and the protease (PR) within the Gag-Pol precursor. This flexible, 68-amino-acid HIV-1 p6* domain has been suggested to negatively interfere with HIV PR activity in vitro proposing a contribution of either the C-terminal p6* tetrapeptide, internal cryptic PR cleavage sites, or a zymogen-related mechanism to a regulated PR activation. To assess these hypotheses in the viral context, a series of recombinant HX10-based provirus constructs has been established with clustered amino acid substitutions throughout the entire p6* coding sequence. Comparative analysis of the mutant proviral clones in different cell culture systems revealed that mutations within the well-conserved amino-terminal p6* region modified the Gag/Gag-Pol ratio and thus resulted in the release of viruses with impaired infectivity. Clustered amino acid substitutions destroying (i) the predicted cryptic PR cleavage sites or (ii) homologies to the pepsinogen propeptide did not influence viral replication in cell culture, whereas substitutions of the carboxyl-terminal p6* residues 62 to 68 altering proper release of the mature PR from the Gag-Pol precursor drastically reduced viral infectivity. Thus, the critical contribution of p6* and overlapping -acting sequence elements to timely regulated virus maturation and infectivity is closely linked to precise ribosomal frameshifting and proper N-terminal release of the viral PR from the Gag-Pol precursor, clearly disproving the hypothesis that sequence motifs in the central part of p6* modulate PR activation and viral infectivity.
    Keywords: P6pol ; Transframe Protein ; HIV-1 ; Frameshift ; Gag-Pol ; Cleavage Site ; Protease Regulation ; Maturation ; Protease Activation ; Biology
    ISSN: 0042-6822
    E-ISSN: 1096-0341
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  • 2
    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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  • 3
    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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  • 4
    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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  • 5
    Language: English
    In: Journal of virology, October 2013, Vol.87(19), pp.10763-76
    Description: In the canonical STAT3 signaling pathway, binding of agonist to receptors activates Janus kinases that phosphorylate cytoplasmic STAT3 at tyrosine 705 (Y705). Phosphorylated STAT3 dimers accumulate in the nucleus and drive the expression of genes involved in inflammation, angiogenesis, invasion, and proliferation. Here, we demonstrate that human cytomegalovirus (HCMV) infection rapidly promotes nuclear localization of STAT3 in the absence of robust phosphorylation at Y705. Furthermore, infection disrupts interleukin-6 (IL-6)-induced phosphorylation of STAT3 and expression of a subset of IL-6-induced STAT3-regulated genes, including SOCS3. We show that the HCMV 72-kDa immediate-early 1 (IE1) protein associates with STAT3 and is necessary to localize STAT3 to the nucleus during infection. Furthermore, expression of IE1 is sufficient to disrupt IL-6-induced phosphorylation of STAT3, binding of STAT3 to the SOCS3 promoter, and SOCS3 gene expression. Finally, inhibition of STAT3 nuclear localization or STAT3 expression during infection is linked to diminished HCMV genome replication. Viral gene expression is also disrupted, with the greatest impact seen following viral DNA synthesis. Our study identifies IE1 as a new regulator of STAT3 intracellular localization and IL-6 signaling and points to an unanticipated role of STAT3 in HCMV infection.
    Keywords: Cell Nucleus -- Metabolism ; Cytomegalovirus -- Physiology ; Cytomegalovirus Infections -- Virology ; Immediate-Early Proteins -- Metabolism ; Interleukin-6 -- Metabolism ; Stat3 Transcription Factor -- Metabolism
    E-ISSN: 1098-5514
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  • 6
    Language: English
    In: PLoS Pathogens, 01 July 2016, Vol.12(7), p.e1005748
    Description: The human cytomegalovirus (hCMV) major immediate-early 1 protein (IE1) is best known for activating transcription to facilitate viral replication. Here we present transcriptome data indicating that IE1 is as significant a repressor as it is an activator of host gene expression. Human cells...
    Keywords: Biology
    ISSN: 1553-7366
    E-ISSN: 1553-7374
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  • 7
    Language: English
    In: Journal of virology, January 2014, Vol.88(2), pp.1228-48
    Description: The 72-kDa immediate early 1 (IE1) protein encoded by human cytomegalovirus (hCMV) is a nuclearly localized promiscuous regulator of viral and cellular transcription. IE1 has long been known to associate with host mitotic chromatin, yet the mechanisms underlying this interaction have not been specified. In this study, we identify the cellular chromosome receptor for IE1. We demonstrate that the viral protein targets human nucleosomes by directly binding to core histones in a nucleic acid-independent manner. IE1 exhibits two separable histone-interacting regions with differential binding specificities for H2A-H2B and H3-H4. The H2A-H2B binding region was mapped to an evolutionarily conserved 10-amino-acid motif within the chromatin-tethering domain (CTD) of IE1. Results from experimental approaches combined with molecular modeling indicate that the IE1 CTD adopts a β-hairpin structure, docking with the acidic pocket formed by H2A-H2B on the nucleosome surface. IE1 binds to the acidic pocket in a way similar to that of the latency-associated nuclear antigen (LANA) of the Kaposi's sarcoma-associated herpesvirus. Consequently, the IE1 and LANA CTDs compete for binding to nucleosome cores and chromatin. Our work elucidates in detail how a key viral regulator is anchored to human chromosomes and identifies the nucleosomal acidic pocket as a joint target of proteins from distantly related viruses. Based on the striking similarities between the IE1 and LANA CTDs and the fact that nucleosome targeting by IE1 is dispensable for productive replication even in "clinical" strains of hCMV, we speculate that the two viral proteins may serve analogous functions during latency of their respective viruses.
    Keywords: Chromosomes, Human -- Virology ; Cytomegalovirus -- Metabolism ; Cytomegalovirus Infections -- Virology ; Immediate-Early Proteins -- Metabolism ; Nucleosomes -- Metabolism
    ISSN: 0022538X
    E-ISSN: 1098-5514
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  • 8
    Language: English
    In: Virology, 15 March 2000, Vol.268(2), pp.294-307
    Description: Recent analyses suggest that the p24 capsid (p24CA) domain of the HIV-1 group-specific antigen (Gag) may be divided into two structurally and functionally distinct moieties: (i) an amino-terminal portion, previously shown to bind the cellular chaperone cyclophilin A, and (ii) a carboxy-terminal domain, known to contribute to the interaction of the Gag and Gag-Pol precursors during the early assembly process. In order to gain deeper insight into the role of the amino-terminal domain of the p24CA protein during viral replication, eight highly conserved proline residues known to promote turns and to terminate -helices within the p24 tertiary structure were replaced by a leucine residue (P-position-L). Following transfection of the proviral constructs in COS7 cells, the majority of the mutants resembled wild-type viruses with respect to the assembly and release of virions. However, although the released particles contained wild-type levels of genomic viral RNA, the mature products of the Gag and Gag-Pol polyproteins as well as the Env glycoproteins—all of them, except mutant P225L—were either noninfectious or severely affected in their replicative capacity. Entry assays monitoring the process of viral DNA synthesis led to the classification of selected provirus mutants into four different phenotypes: (i) mutant P225L was infectious and allowed complete reverse transcription including formation of 2-LTR circles; (ii) mutants P149L, P170L, and P217L failed to form 2-LTR circles; (iii) mutant P222L displayed a severe defect in binding and incorporating cyclophilin A into virions, was delayed with respect to DNA polymerization, and failed to form a 2-LTR replication intermediate; and (iv) mutant P133L was unable even to synthesize a first-strand cDNA product. All replication-defective mutants were characterized by severe alterations in the stability of virion cores, which were in two cases reflected by visible changes in the core morphology. These results suggest that proline residues in the NH2-terminal capsid domain represent critical structure determinants for proper formation of functional virion cores and subsequent stages of early replication. Copyright 2000 Academic Press.
    Keywords: HIV-1 ; Capsid ; Core ; Replication ; Assembly ; Biology
    ISSN: 0042-6822
    E-ISSN: 1096-0341
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  • 9
    Language: English
    In: Reviews in Medical Virology, January 2010, Vol.20(1), pp.34-50
    Description: The double‐stranded DNA genomes of herpesviruses exist in at least three alternative global chromatin states characterised by distinct nucleosome content. When encapsidated in virus particles, the viral DNA is devoid of any nucleosomes. In contrast, within latently infected nuclei herpesvirus genomes are believed to form regular nucleosomal structures resembling cellular chromatin. Finally, during productive infection nuclear viral DNA appears to adopt a state of intermediate chromatin formation with irregularly spaced nucleosomes. Nucleosome occupancy coupled with posttranslational histone modifications and other epigenetic marks may contribute significantly to the extent and timing of transcription from the viral genome and, consequently, to the outcome of infection. Recent research has provided first insights into the viral and cellular mechanisms that either maintain individual herpesvirus chromatin states or mediate transition between them. Here, we summarise and discuss both early work and new developments pointing towards common principles pertinent to the dynamic structure and epigenetic regulation of herpesvirus chromatin. Special emphasis is given to the emerging similarities in nucleosome assembly and disassembly processes on herpes simplex virus type 1 and human cytomegalovirus genomes over the course of the viral productive replication cycle and during the switch between latent and lytic infectious stages. Copyright © 2009 John Wiley & Sons, Ltd.
    Keywords: Genomes ; Latent Infection ; Nucleosomes ; Histones ; Chromatin ; Replication ; Epigenetics ; DNA ; Transcription ; Nuclei ; Infection ; Human Cytomegalovirus ; Herpesvirus ; Herpes Simplex Virus 1 ; Human Cytomegalovirus ; Herpesvirus ; Herpes Simplex Virus 1 ; Chromatin ; DNA ; Genomes ; Histones ; Infection ; Latent Infection ; Nuclei ; Nucleosomes ; Replication ; Transcription ; Epigenetics ; Replication;
    ISSN: 1052-9276
    E-ISSN: 1099-1654
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