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Journal articleSerrao E, Ballandras-Colas A, Cherepanov P, et al., 2015,
Key determinants of target DNA recognition by retroviral intasomes
, Retrovirology, Vol: 12, ISSN: 1742-4690Background: Retroviral integration favors weakly conserved palindrome sequences at the sites of viral DNA joiningand generates a short (4–6 bp) duplication of host DNA flanking the provirus. We previously determined two keyparameters that underlie the target DNA preference for prototype foamy virus (PFV) and human immunodeficiencyvirus type 1 (HIV-1) integration: flexible pyrimidine (Y)/purine (R) dinucleotide steps at the centers of the integrationsites, and base contacts with specific integrase residues, such as Ala188 in PFV integrase and Ser119 in HIV-1 integrase.Here we examined the dinucleotide preference profiles of a range of retroviruses and correlated these findings withrespect to length of target site duplication (TSD).Results: Integration datasets covering six viral genera and the three lengths of TSD were accessed from the literatureor generated in this work. All viruses exhibited significant enrichments of flexible YR and/or selection against rigid RYdinucleotide steps at the centers of integration sites, and the magnitude of this enrichment inversely correlated withTSD length. The DNA sequence environments of in vivo-generated HIV-1 and PFV sites were consistent with integrationinto nucleosomes, however, the local sequence preferences were largely independent of target DNA chromatinization.Integration sites derived from cells infected with the gammaretrovirus reticuloendotheliosis virus strain A (Rev-A),which yields a 5 bp TSD, revealed the targeting of global chromatin features most similar to those of Moloneymurine leukemia virus, which yields a 4 bp duplication. In vitro assays revealed that Rev-A integrase interacts withand is catalytically stimulated by cellular bromodomain containing 4 protein.Conclusions: Retroviral integrases have likely evolved to bend target DNA to fit scissile phosphodiester bondsinto two active sites for integration, and viruses that cut target DNA with a 6 bp stagger may not need to bendDNA as sharply as viruses tha
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Journal articleFoerster A, Maertens GN, Farrell PJ, et al., 2015,
Dimerization of Matrix Protein Is Required for Budding of Respiratory Syncytial Virus
, Journal of Virology, Vol: 89, Pages: 4624-4635, ISSN: 1098-5514Respiratory syncytial virus (RSV) infects epithelial cells of the respiratory tract and is a major cause of bronchiolitis and pneumonia in children and the elderly. The virus assembles and buds through the plasma membrane, forming elongated membrane filaments, but details of how this happens remain obscure. Oligomerization of the matrix protein (M) is a key step in the process of assembly and infectious virus production. In addition, it was suggested to affect the conformation of the fusion protein, the major current target for RSV antivirals, in the mature virus. The structure and assembly of M are thus key parameters in the RSV antiviral development strategy. The structure of RSV M was previously published as a monomer. Other paramyxovirus M proteins have been shown to dimerize, and biochemical data suggest that RSV M also dimerizes. Here, using size exclusion chromatography-multiangle laser light scattering, we show that the protein is dimeric in solution. We also crystallized M in two crystal forms and show that it assembles into equivalent dimers in both lattices. Dimerization interface mutations destabilize the M dimer in vitro. To assess the biological relevance of dimerization, we used confocal imaging to show that dimerization interface mutants of M fail to assemble into viral filaments on the plasma membrane. Additionally, budding and release of virus-like particles are prevented in M mutants that fail to form filaments. Importantly, we show that M is biologically active as a dimer and that the switch from M dimers to higher-order oligomers triggers viral filament assembly and virus production.
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Journal articleSun C, Schattgen SA, Pisitkun P, et al., 2015,
Evasion of Innate Cytosolic DNA Sensing by a Gammaherpesvirus Facilitates Establishment of Latent Infection
, JOURNAL OF IMMUNOLOGY, Vol: 194, Pages: 1819-1831, ISSN: 0022-1767- Cite
- Citations: 82
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Journal articleAllday MJ, Bazot Q, White RE, 2015,
The EBNA3 Family: Two Oncoproteins and a Tumour Suppressor that Are Central to the Biology of EBV in B Cells
, EPSTEIN BARR VIRUS, VOL 2: ONE HERPES VIRUS: MANY DISEASES, Vol: 391, Pages: 61-117, ISSN: 0070-217X- Author Web Link
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- Citations: 61
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Journal articleFarrell PJ, 2015,
Epstein-Barr Virus Strain Variation
, EPSTEIN BARR VIRUS, VOL 1: ONE HERPES VIRUS: MANY DISEASES, Vol: 390, Pages: 45-69, ISSN: 0070-217X- Author Web Link
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- Citations: 41
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Journal articleLong JS, Benfield CT, Barclay WS, 2014,
One-way trip: Influenza virus' adaptation to gallinaceous poultry may limit its pandemic potential
, Bioessays, Vol: 37, Pages: 204-212, ISSN: 1521-1878We hypothesise that some influenza virus adaptations to poultry may explain why the barrier for human-to-human transmission is not easily overcome once the virus has crossed from wild birds to chickens. Since the cluster of human infections with H5N1 influenza in Hong Kong in 1997, chickens have been recognized as the major source of avian influenza virus infection in humans. Although often severe, these infections have been limited in their subsequent human-to-human transmission, and the feared H5N1 pandemic has not yet occurred. Here we examine virus adaptations selected for during replication in chickens and other gallinaceous poultry. These include altered receptor binding and increased pH of fusion of the haemagglutinin as well as stalk deletions of the neuraminidase protein. This knowledge could aid the delivery of vaccines and increase our ability to prioritize research efforts on those viruses from the diverse array of avian influenza viruses that have greatest human pandemic potential.
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Journal articlePekkonen P, Jarviluoma A, Zinovkina N, et al., 2014,
KSHV viral cyclin interferes with T-cell development and induces lymphoma through Cdk6 and Notch activation in vivo
, CELL CYCLE, Vol: 13, Pages: 3670-3684, ISSN: 1538-4101- Author Web Link
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- Citations: 18
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Journal articlePaudel BP, Rueda D, 2014,
Molecular Crowding Accelerates Ribozyme Docking and Catalysis
, Journal of the American Chemical Society, Vol: 136, Pages: 16700-16703, ISSN: 1520-5126All biological processes take place in highly crowded cellular environments. However, the effect that molecular crowding agents have on the folding and catalytic properties of RNA molecules remains largely unknown. Here, we have combined single-molecule fluorescence resonance energy transfer (smFRET) and bulk cleavage assays to determine the effect of a molecular crowding agents on the folding and catalysis of a model RNA enzyme, the hairpin ribozyme. Our single-molecule data reveal that PEG favors the formation of the docked (active) structure by increasing the docking rate constant with increasing PEG concentrations. Furthermore, Mg2+ ion-induced folding in the presence of PEG occurs at concentrations ∼7-fold lower than in the absence of PEG, near the physiological range (∼1 mM). Lastly, bulk cleavage assays in the presence of the crowding agent show that the ribozyme’s activity increases while the heterogeneity decreases. Our data is consistent with the idea that molecular crowding plays an important role in the stabilization of ribozyme active conformations in vivo.
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Journal articleElderfield RA, Watson SJ, Godlee A, et al., 2014,
Accumulation of human-adapting mutations during circulation of A(H1N1)pdm09 influenza virus in humans in the United Kingdom.
, Journal of virology, Vol: 88, Pages: 13269-13283, ISSN: 0022-538X<h4>Unlabelled</h4>The influenza pandemic that emerged in 2009 provided an unprecedented opportunity to study adaptation of a virus recently acquired from an animal source during human transmission. In the United Kingdom, the novel virus spread in three temporally distinct waves between 2009 and 2011. Phylogenetic analysis of complete viral genomes showed that mutations accumulated over time. Second- and third-wave viruses replicated more rapidly in human airway epithelial (HAE) cells than did the first-wave virus. In infected mice, weight loss varied between viral isolates from the same wave but showed no distinct pattern with wave and did not correlate with viral load in the mouse lungs or severity of disease in the human donor. However, second- and third-wave viruses induced less alpha interferon in the infected mouse lungs. NS1 protein, an interferon antagonist, had accumulated several mutations in second- and third-wave viruses. Recombinant viruses with the third-wave NS gene induced less interferon in human cells, but this alone did not account for increased virus fitness in HAE cells. Mutations in HA and NA genes in third-wave viruses caused increased binding to α-2,6-sialic acid and enhanced infectivity in human mucus. A recombinant virus with these two segments replicated more efficiently in HAE cells. A mutation in PA (N321K) enhanced polymerase activity of third-wave viruses and also provided a replicative advantage in HAE cells. Therefore, multiple mutations allowed incremental changes in viral fitness, which together may have contributed to the apparent increase in severity of A(H1N1)pdm09 influenza virus during successive waves.<h4>Importance</h4>Although most people infected with the 2009 pandemic influenza virus had mild or unapparent symptoms, some suffered severe and devastating disease. The reasons for this variability were unknown, but the numbers of severe cases increased during successive waves of human infection i
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Journal articleJia N, Barclay WS, Roberts K, et al., 2014,
Glycomic characterization of respiratory tract tissues of ferrets IMPLICATIONS FOR ITS USE IN INFLUENZA VIRUS INFECTION STUDIES
, Journal of Biological Chemistry, Vol: 289, Pages: 28489-28504, ISSN: 0021-9258The initial recognition between influenza virus and the host cell is mediated by interactions between the viral surface protein hemagglutinin and sialic acid-terminated glycoconjugates on the host cell surface. The sialic acid residues can be linked to the adjacent monosaccharide by α2–3- or α2–6-type glycosidic bonds. It is this linkage difference that primarily defines the species barrier of the influenza virus infection with α2–3 binding being associated with avian influenza viruses and α2–6 binding being associated with human strains. The ferret has been extensively used as an animal model to study the transmission of influenza. To better understand the validity of this model system, we undertook glycomic characterization of respiratory tissues of ferret, which allows a comparison of potential viral receptors to be made between humans and ferrets. To complement the structural analysis, lectin staining experiments were performed to characterize the regional distributions of glycans along the respiratory tract of ferrets. Finally, the binding between the glycans identified and the hemagglutinins of different strains of influenza viruses was assessed by glycan array experiments. Our data indicated that the respiratory tissues of ferret heterogeneously express both α2–3- and α2–6-linked sialic acids. However, the respiratory tissues of ferret also expressed the Sda epitope (NeuAcα2-3(GalNAcβ1–4)Galβ1–4GlcNAc) and sialylated N,N′-diacetyllactosamine (NeuAcα2–6GalNAcβ1–4GlcNAc), which have not been observed in the human respiratory tract surface epithelium. The presence of the Sda epitope reduces potential binding sites for avian viruses and thus may have implications for the usefulness of the ferret in the study of influenza virus infection.
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