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  • 1
    Keywords: NF-KAPPA-B ; PHOSPHORYLATION ; IDENTIFICATION ; HUMAN CYTOMEGALOVIRUS ; SARCOMA-ASSOCIATED HERPESVIRUS ; EA-D ; RNA-SEQ ; LYTIC DNA-REPLICATION ; LATE PROMOTER ; TRANSACTIVATION ACTIVITY
    Abstract: The mechanism regulating expression of late genes, encoding viral structural components, is an unresolved problem in the biology of DNA tumor viruses. Here we show that BGLF4, the only protein kinase encoded by Epstein-Barr virus (EBV), controls expression of late genes independent of its effect on viral DNA replication. Ectopic expression of BGLF4 in cells lacking the kinase gene stimulated the transcript levels of six late genes by 8- to 10-fold. Introduction of a BGLF4 mutant that eliminated its kinase activity did not stimulate late gene expression. In cells infected with wild-type EBV, siRNA to BGLF4 (siG4) markedly reduced late gene expression without compromising viral DNA replication. Synthesis of late products was restored upon expression of a form of BGLF4 resistant to the siRNA. Studying the EBV transcriptome using mRNA-seq during the late phase of the lytic cycle in the absence and presence of siG4 showed that BGLF4 controlled expression of 31 late genes. Analysis of the EBV transcriptome identified BGLF3 as a gene whose expression was reduced as a result of silencing BGLF4. Knockdown of BGLF3 markedly reduced late gene expression but had no effect on viral DNA replication or expression of BGLF4. Our findings reveal the presence of a late control locus encompassing BGLF3 and BGLF4 in the EBV genome, and provide evidence for the importance of both proteins in post-replication events that are necessary for expression of late genes.
    Type of Publication: Journal article published
    PubMed ID: 25166506
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  • 2
    Keywords: CELLS ; IN-VITRO ; CELL ; Germany ; KINASE ; DISEASE ; DISEASES ; PROTEIN ; MICE ; RELEASE ; COMPLEX ; COMPLEXES ; PHOSPHORYLATION ; PROTEIN-KINASE ; ALPHA ; culture ; TRANSPORT ; virus ; cytoskeleton ; DEGRADATION ; MINUTE VIRUS ; NONSTRUCTURAL PROTEIN NS1 ; REPLICATION ; REPLICATIVE FUNCTIONS ; autonomous parvovirus ; SAN-FRANCISCO ; VESICLES ; ASSEMBLIES ; assembly ; parvovirus ; USA ; gelsolin ; INFECTIOUS-DISEASES ; EXPORT ; microbiology ; ACTIN ; PARVOVIRUS MINUTE VIRUS ; MEDIA ; H1PV ; PKC-ETA ; POLYMERIZATION ; VIRAL INTERACTIONS
    Abstract: The autonomous parvovirus Minute Virus of Mice (MVM) induces specific changes in the cytoskeleton filaments of infected permissive cells, causing in particular the degradation of actin fibers and the generation of "actin patches.'' This is attributed to a virus-induced imbalance between the polymerization factor N-WASP (Wiscott-Aldrich syndrome protein) and gelsolin, a multifunctional protein cleaving actin filaments. Here, the focus is on the involvement of gelsolin in parvovirus propagation and virus-induced actin processing. Gelsolin activity was knocked-down, and consequences thereof were determined for virus replication and egress and for actin network integrity. Though not required for virus replication or progeny particle assembly, gelsolin was found to control MVM (and related H1-PV) transport from the nucleus to the cell periphery and release into the culture medium. Gelsolin-dependent actin degradation and progeny virus release were both controlled by (NS1)/CKII alpha, a recently identified complex between a cellular protein kinase and a MVM non-structural protein. Furthermore, the export of newly synthesized virions through the cytoplasm appeared to be mediated by (virus-modified) lysomal/late endosomal vesicles. By showing that MVM release, like entry, is guided by the cytoskeleton and mediated by vesicles, these results challenge the current view that egress of non-enveloped lytic viruses is a passive process
    Type of Publication: Journal article published
    PubMed ID: 18704167
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  • 3
    Keywords: Germany ; human ; DISEASE ; DISEASES ; HISTORY ; POPULATION ; DISTINCT ; PROTEIN ; TIME ; INFECTION ; SKIN ; papillomavirus ; ALPHA ; antibodies ; antibody ; PATTERNS ; AGE ; WOMEN ; MEN ; CAPSID PROTEIN ; human papillomavirus ; VIRUS-LIKE PARTICLES ; HIGH-RISK ; HPV ; BETA ; HUMAN-PAPILLOMAVIRUS ; Jun ; SQUAMOUS-CELL CARCINOMA ; POLYMERASE-CHAIN-REACTION ; L1 ; CHILDREN ; NATURAL-HISTORY ; PREVALENCE ; NONMELANOMA SKIN CANCERS ; glutathione-S-transferase ; SERUM ; ADULT ; ADULTS ; SAN-FRANCISCO ; review ; RE ; PATTERN ; papillomaviruses ; GAMMA ; EPIDERMODYSPLASIA-VERRUCIFORMIS ; HPV 16 ; USA ; YOUNG-ADULTS ; INFECTIOUS-DISEASES ; microbiology ; serology ; multiplex serology ; SEROPREVALENCE ; GENERAL-POPULATION ; HPV types ; MAJOR CAPSID PROTEIN ; HPV-16 ; CUTANEOUS HUMAN PAPILLOMAVIRUSES ; FOOD-CONSUMPTION HABITS ; NORMAL CERVICAL SMEARS
    Abstract: The natural history of infections with many human papillomavirus (HPV) types is poorly understood. Here, we describe for the first time the age-and sex-dependent antibody prevalence for 29 cutaneous and five mucosal HPV types from 15 species within five phylogenetic genera (alpha, beta, gamma, mu, nu) in a general population. Sera from 1,797 German adults and children (758 males and 1,039 females) between 1 and 82 years (median 37 years) were analysed for antibodies to the major capsid protein L1 by Luminex-based multiplex serology. The first substantial HPV antibody reactions observed already in children and young adults are those to cutaneous types of the genera nu (HPV 41) and mu (HPV 1, 63). The antibody prevalence to mucosal high-risk types, most prominently HPV 16, was elevated after puberty in women but not in men and peaked between 25 and 34 years. Antibodies to beta and gamma papillomaviruses (PV) were rare in children and increased homogeneously with age, with prevalence peaks at 40 and 60 years in women and 50 and 70 years in men. Antibodies to cutaneous alpha PV showed a heterogeneous age distribution. In summary, these data suggest three major seroprevalence patterns for HPV of phylogenetically distinct genera: antibodies to mu and nu skin PV appear early in life, those to mucosal alpha PV in women after puberty, and antibodies to beta as well as to gamma skin PV accumulate later in life
    Type of Publication: Journal article published
    PubMed ID: 18566657
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  • 4
    Keywords: CELLS ; EXPRESSION ; CELL ; screening ; DISEASE ; DISEASES ; GENE ; GENOME ; PROTEIN ; PROTEINS ; RNA ; SACCHAROMYCES-CEREVISIAE ; LINES ; TIME ; DNA ; INFECTION ; MOTIFS ; INDUCTION ; BINDING ; CELL-LINES ; CYCLE ; DOWN-REGULATION ; SEQUENCE ; TARGET ; virus ; DELETION ; ELEMENT ; IDENTIFICATION ; IN-SITU ; CELL-LINE ; LYMPHOCYTES ; DISPLAY ; LOCALIZATION ; B-CELLS ; STABILITY ; DNA-REPLICATION ; cell lines ; RIBOSOMAL-RNA ; EPSTEIN-BARR-VIRUS ; Epstein-Barr virus ; SAN-FRANCISCO ; MOTIF ; LIBRARIES ; mRNA ; LEVEL ; nucleolus ; LIBRARY ; USA ; B-CELL ; PRECURSOR ; BACTERIA ; VIRAL-DNA ; NONCODING RNAS ; virology ; GENOMES ; POLYMERASE ; Genetic ; WELL ; DNA polymerase ; Lymphoblastoid cell lines ; ENCODED MICRORNAS ; MARMOSET LEUKOCYTES ; NON-MESSENGER RNAS ; PRERIBOSOMAL RNA ; SMALL NUCLEAR ; TRANSFORMED T-CELLS
    Abstract: Small nucleolar RNAs (snoRNAs) are localized within the nucleolus, a sub-nuclear compartment, in which they guide ribosomal or spliceosomal RNA modifications, respectively. Up until now, snoRNAs have only been identified in eukaryal and archaeal genomes, but are notably absent in bacteria. By screening B lymphocytes for expression of non-coding RNAs (ncRNAs) induced by the Epstein-Barr virus (EBV), we here report, for the first time, the identification of a snoRNA gene within a viral genome, designated as v-snoRNA1. This genetic element displays all hallmark sequence motifs of a canonical C/D box snoRNA, namely C/C'-as well as D/D'-boxes. The nucleolar localization of v-snoRNA1 was verified by in situ hybridisation of EBV-infected cells. We also confirmed binding of the three canonical snoRNA proteins, fibrillarin, Nop56 and Nop58, to v-snoRNA1. The C-box motif of v-snoRNA1 was shown to be crucial for the stability of the viral snoRNA; its selective deletion in the viral genome led to a complete down-regulation of v-snoRNA1 expression levels within EBV-infected B cells. We further provide evidence that v-snoRNA1 might serve as a miRNA-like precursor, which is processed into 24 nt sized RNA species, designated as v-snoRNA1(24pp). A potential target site of v-snoRNA1(24pp) was identified within the 3'-UTR of BALF5 mRNA which encodes the viral DNA polymerase. V-snoRNA1 was found to be expressed in all investigated EBV-positive cell lines, including lymphoblastoid cell lines (LCL). Interestingly, induction of the lytic cycle markedly up-regulated expression levels of v-snoRNA1 up to 30-fold. By a computational approach, we identified a v-snoRNA1 homolog in the rhesus lymphocryptovirus genome. This evolutionary conservation suggests an important role of v-snoRNA1 during gamma-herpesvirus infection
    Type of Publication: Journal article published
    PubMed ID: 19680535
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  • 5
  • 6
    Keywords: MICROSCOPY ; PROTEINS ; PARTICLES ; LIVE CELLS ; IMMUNODEFICIENCY-VIRUS TYPE-1 ; MEMBRANE-BINDING ; MICRODOMAINS ; VPU ; CELL BIOLOGY ; GAG MULTIMERIZATION
    Abstract: Assembly and release of human immunodeficiency virus (HIV) occur at the plasma membrane of infected cells and are driven by the Gag polyprotein. Previous studies analyzed viral morphogenesis using biochemical methods and static images, while dynamic and kinetic information has been lacking until very recently. Using a combination of wide-field and total internal reflection fluorescence microscopy, we have investigated the assembly and release of fluorescently labeled HIV-1 at the plasma membrane of living cells with high time resolution. Gag assembled into discrete clusters corresponding to single virions. Formation of multiple particles from the same site was rarely observed. Using a photoconvertible fluorescent protein fused to Gag, we determined that assembly was nucleated preferentially by Gag molecules that had recently attached to the plasma membrane or arrived directly from the cytosol. Both membrane-bound and cytosol derived Gag polyproteins contributed to the growing bud. After their initial appearance, assembly sites accumulated at the plasma membrane of individual cells over 1-2 hours. Assembly kinetics were rapid: the number of Gag molecules at a budding site increased, following a saturating exponential with a rate constant of similar to 5x10(-3) s(-1), corresponding to 8- 9 min for 90% completion of assembly for a single virion. Release of extracellular particles was observed at similar to 1,500 +/- 700 s after the onset of assembly. The ability of the virus to recruit components of the cellular ESCRT machinery or to undergo proteolytic maturation, or the absence of Vpu did not significantly alter the assembly kinetics.
    Type of Publication: Journal article published
    PubMed ID: 19893629
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  • 7
    Abstract: The triggers of autoimmune diseases such as multiple sclerosis (MS) remain elusive. Epidemiological studies suggest that common pathogens can exacerbate and also induce MS, but it has been difficult to pinpoint individual organisms. Here we demonstrate that in vivo clonally expanded CD4+ T cells isolated from the cerebrospinal fluid of a MS patient during disease exacerbation respond to a poly-arginine motif of the nonpathogenic and ubiquitous Torque Teno virus. These T cell clones also can be stimulated by arginine-enriched protein domains from other common viruses and recognize multiple autoantigens. Our data suggest that repeated infections with common pathogenic and even nonpathogenic viruses could expand T cells specific for conserved protein domains that are able to cross-react with tissue-derived and ubiquitous autoantigens.
    Type of Publication: Journal article published
    PubMed ID: 16362076
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  • 8
    Keywords: EXPRESSION ; proliferation ; GENE-EXPRESSION ; PROTEIN ; DNA ; INFECTION ; IDENTIFICATION ; CELL-LINE ; REPLICATION ; EPSTEIN-BARR-VIRUS ; RNAS ; LYMPHOCYTE-TRANSFORMATION
    Abstract: Epstein-Barr virus (EBV), an oncogenic human herpesvirus, induces cell proliferation after infection of resting B lymphocytes, its reservoir in vivo. The viral latent proteins are necessary for permanent B cell growth, but it is unknown whether they are sufficient. EBV was recently found to encode microRNAs (miRNAs) that are expressed in infected B cells and in some EBV-associated lymphomas. EBV miRNAs are grouped into two clusters located either adjacent to the BHRF1 gene or in introns contained within the viral BART transcripts. To understand the role of the BHRF1 miRNA cluster, we have constructed a virus mutant that lacks all its three members (delta123) and a revertant virus. Here we show that the B cell transforming capacity of the delta123 EBV mutant is reduced by more than 20-fold, relative to wild type or revertant viruses. B cells exposed to the knock-out virus displayed slower growth, and exhibited a two-fold reduction in the percentage of cells entering the cell cycle S phase. Furthermore, they displayed higher latent gene expression levels and latent protein production than their wild type counterparts. Therefore, the BHRF1 miRNAs accelerate B cell expansion at lower latent gene expression levels. Thus, this miRNA cluster simultaneously enhances expansion of the virus reservoir and reduces the viral antigenic load, two features that have the potential to facilitate persistence of the virus in the infected host. Thus, the EBV BHRF1 miRNAs may represent new therapeutic targets for the treatment of some EBV-associated lymphomas.
    Type of Publication: Journal article published
    PubMed ID: 21379335
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  • 9
    Keywords: CELLS ; proliferation ; IN-VIVO ; GENE ; EBV INFECTION ; GERMINAL-CENTER ; HUMAN LYMPHOCYTES-B ; RECEPTOR CR-2 ; CLASS SWITCH RECOMBINATION ; ABERRANT SOMATIC HYPERMUTATION ; CYTIDINE DEAMINASE AID ; HYPER-IGM SYNDROME ; POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDERS ; VARIABLE REGION GENES
    Abstract: Epstein-Barr virus (EBV), a lymphomagenic human herpesvirus, colonises the host through polyclonal B cell-growth-transforming infections yet establishes persistence only in IgD(+) CD27(+) non-switched memory (NSM) and IgD(-) CD27(+) switched memory (SM) B cells, not in IgD(+) CD27(-) naive (N) cells. How this selectivity is achieved remains poorly understood. Here we show that purified N, NSM and SM cell preparations are equally transformable in vitro to lymphoblastoid cells lines (LCLs) that, despite upregulating the activation-induced cytidine deaminase (AID) enzyme necessary for Ig isotype switching and Ig gene hypermutation, still retain the surface Ig phenotype of their parental cells. However, both N- and NSM-derived lines remain inducible to Ig isotype switching by surrogate T cell signals. More importantly, IgH gene analysis of N cell infections revealed two features quite distinct from parallel mitogen-activated cultures. Firstly, following 4 weeks of EBV-driven polyclonal proliferation, individual clonotypes then become increasingly dominant; secondly, in around 35% cases these clonotypes carry Ig gene mutations which both resemble AID products and, when analysed in prospectively-harvested cultures, appear to have arisen by sequence diversification in vitro. Thus EBV infection per se can drive at least some naive B cells to acquire Ig memory genotypes; furthermore, such cells are often favoured during an LCL's evolution to monoclonality. Extrapolating to viral infections in vivo, these findings could help to explain how EBV-infected cells become restricted to memory B cell subsets and why EBV-driven lymphoproliferative lesions, in primary infection and/or immunocompromised settings, so frequently involve clones with memory genotypes.
    Type of Publication: Journal article published
    PubMed ID: 22589726
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  • 10
    Keywords: PROTEIN FAMILY ; PLASMODIUM-FALCIPARUM ; MULTIPLE SEQUENCE ALIGNMENT ; HOST-CELLS ; EUKARYOTIC MEMBRANE-TRAFFICKING ; APICOMPLEXAN PARASITES ; ENDOMEMBRANE SYSTEM ; SELECTABLE MARKER ; ENDOCYTIC PATHWAY ; ESCRT MACHINERY
    Abstract: The basic organisation of the endomembrane system is conserved in all eukaryotes and comparative genome analyses provides compelling evidence that the endomembrane system of the last common eukaryotic ancestor (LCEA) is complex with many genes required for regulated traffic being present. Although apicomplexan parasites, causative agents of severe human and animal diseases, appear to have only a basic set of trafficking factors such as Rab-GTPases, they evolved unique secretory organelles (micronemes, rhoptries and dense granules) that are sequentially secreted during invasion of the host cell. In order to define the secretory pathway of apicomplexans, we performed an overexpression screen of Rabs in Toxoplasma gondii and identified Rab5A and Rab5C as important regulators of traffic to micronemes and rhoptries. Intriguingly, we found that not all microneme proteins traffic depends on functional Rab5A and Rab5C, indicating the existence of redundant microneme targeting pathways. Using two-colour super-resolution stimulated emission depletion (STED) we verified distinct localisations of independent microneme proteins and demonstrate that micronemal organelles are organised in distinct subsets or subcompartments. Our results suggest that apicomplexan parasites modify classical regulators of the endocytic system to carryout essential parasite-specific roles in the biogenesis of their unique secretory organelles.
    Type of Publication: Journal article published
    PubMed ID: 23505371
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