Anna Grewer, Martina Bleyer, Kerstin Mätz-Rensing, Alexander S. Hahn, Tim Rüggeberg, Gregor Babaryka, Andre Zimmermann, Stefan Pöhlmann, and Artur Kaul
Emerging Infectious Diseases, Vol 25, Iss 8, Pp 1552-1555 (2019)
Kaposi sarcoma, Kaposi sarcoma herpesvirus, KSHV, nonhuman primate, rhadinovirus, viruses, Medicine, Infectious and parasitic diseases, and RC109-216
We identified a novel Kaposi’s sarcoma herpesvirus–related rhadinovirus (Colobine gammaherpesvirus 1) in a mantled guereza (Colobus guereza kikuyensis). The animal had multiple oral tumors characterized by proliferation of latent nuclear antigen 1–positive spindle cells and was not co-infected with immunosuppressive simian viruses, suggesting that it had Kaposi sarcoma caused by this novel rhadinovirus.
Akshay Dhingra, Tina Ganzenmueller, Elias Hage, Nicolás M. Suárez, Kerstin Mätz-Rensing, Dimitri Widmer, Stefan Pöhlmann, Andrew J. Davison, Thomas F. Schulz, and Artur Kaul
Emerging Infectious Diseases, Vol 25, Iss 8, Pp 1548-1551 (2019)
Virology, bioinformatics, evolution, viruses, Kaposi sarcoma, herpesvirus, Medicine, Infectious and parasitic diseases, and RC109-216
We determined the complete genome sequence of a virus isolated from a mantled guereza that died of primary effusion lymphoma. The virus is closely related to Kaposi’s sarcoma–associated herpesvirus (KSHV) but lacks some genes implicated in KSHV pathogenesis. This finding may help determine how KSHV causes primary effusion lymphoma in humans.
Markus Hoffmann, Enrika Schütze, Andreas Bernhard, Lennart Schlaphoff, Artur Kaul, Sandra Schöniger, and Stefan Pöhlmann
Pathogens, Vol 8, Iss 1, p 13 (2019)
pygmy chimpanzee, papillomavirus, sequence evolution, focal epithelial hyperplasia, and Medicine
Pan paniscus Papillomavirus 1 (PpPV1) causes focal epithelial hyperplasia (FEH) in infected animals. Here, we analyzed the present disease manifestation and PpPV1 genomic sequence of an animal that was afflicted by an FEH epizootic outbreak in 1987 for which the sequence of the responsible PpPV1 was determined. The animal displayed FEH more than 30 years after the initial diagnosis, indicating persistence or recurrence of the disease, and evidence for active PpPV1 infection was obtained. Moreover, the sequences of the viral genomes present in the late 1980s and in 2018 differed at 23 nucleotide positions, resulting in 11 amino acid exchanges within coding regions. These findings suggest that PpPV1-induced FEH might not undergo complete and/or permanent remission in a subset of afflicted animals.
Rolf W. Hartmann, Christian D. Klein, Lars Kattner, Ralf Bartenschlager, Artur Kaul, Bernd Kronenberger, Beatrice Albrecht, Sigrid Ziegler, and Marcel Holzer
Molecules, Vol 13, Iss 5, Pp 1081-1110 (2008)
Hepatitis C Virus, CD81-receptor, large extracellular loop, terfenadine derivatives, microwave assisted syntheses., Organic chemistry, and QD241-441
Terfenadine (4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-(4-tert-butylphenyl)-butan-1-ol) was identified in a biological screening to be a moderate inhibitor (27% inhibition) of the CD81-LELÃ¢Â€Â“HCV-E2 interaction. To increase the observed biologicalactivity, 63 terfenadine derivates were synthesized via microwave assisted nucleophilicsubstitution. The prepared compounds were tested for their inhibitory potency by means ofa fluorescence labeled antibody assay using HUH7.5 cells. Distinct structure-activityrelationships could be derived. Optimization was successful, leading to 3g, identfied as themost potent compound (69 % inhibition). Experiments with viral particles revealed thatthere might be additional HCV infection reducing mechanisms.
Julia Diegelmann, Florian Beigel, Kathrin Zitzmann, Artur Kaul, Burkhard Göke, Christoph J Auernhammer, Ralf Bartenschlager, Helmut M Diepolder, and Stephan Brand
PLoS ONE, Vol 5, Iss 12, p e15200 (2010)
Medicine and Science
BACKGROUND:Specific differences in signaling and antiviral properties between the different Lambda-interferons, a novel group of interferons composed of IL-28A, IL-28B and IL-29, are currently unknown. This is the first study comparatively investigating the transcriptome and the antiviral properties of the Lambda-interferons IL-28A and IL-29. METHODOLOGY/PRINCIPAL FINDINGS:Expression studies were performed by microarray analysis, quantitative PCR (qPCR), reporter gene assays and immunoluminometric assays. Signaling was analyzed by Western blot. HCV replication was measured in Huh-7 cells expressing subgenomic HCV replicon. All hepatic cell lines investigated as well as primary hepatocytes expressed both IFN-λ receptor subunits IL-10R2 and IFN-λR1. Both, IL-28A and IL-29 activated STAT1 signaling. As revealed by microarray analysis, similar genes were induced by both cytokines in Huh-7 cells (IL-28A: 117 genes; IL-29: 111 genes), many of them playing a role in antiviral immunity. However, only IL-28A was able to significantly down-regulate gene expression (n = 272 down-regulated genes). Both cytokines significantly decreased HCV replication in Huh-7 cells. In comparison to liver biopsies of patients with non-viral liver disease, liver biopsies of patients with HCV showed significantly increased mRNA expression of IL-28A and IL-29. Moreover, IL-28A serum protein levels were elevated in HCV patients. In a murine model of viral hepatitis, IL-28 expression was significantly increased. CONCLUSIONS/SIGNIFICANCE:IL-28A and IL-29 are up-regulated in HCV patients and are similarly effective in inducing antiviral genes and inhibiting HCV replication. In contrast to IL-29, IL-28A is a potent gene repressor. Both IFN-λs may have therapeutic potential in the treatment of chronic HCV.
Artur Kaul, Sarah Stauffer, Carola Berger, Thomas Pertel, Jennifer Schmitt, Stephanie Kallis, Margarita Zayas, Volker Lohmann, Jeremy Luban, and Ralf Bartenschlager
PLoS Pathogens, Vol 5, Iss 8, p e1000546 (2009)
Immunologic diseases. Allergy, RC581-607, Biology (General), and QH301-705.5
Viruses are obligate intracellular parasites and therefore their replication completely depends on host cell factors. In case of the hepatitis C virus (HCV), a positive-strand RNA virus that in the majority of infections establishes persistence, cyclophilins are considered to play an important role in RNA replication. Subsequent to the observation that cyclosporines, known to sequester cyclophilins by direct binding, profoundly block HCV replication in cultured human hepatoma cells, conflicting results were obtained as to the particular cyclophilin (Cyp) required for viral RNA replication and the underlying possible mode of action. By using a set of cell lines with stable knock-down of CypA or CypB, we demonstrate in the present work that replication of subgenomic HCV replicons of different genotypes is reduced by CypA depletion up to 1,000-fold whereas knock-down of CypB had no effect. Inhibition of replication was rescued by over-expression of wild type CypA, but not by a mutant lacking isomerase activity. Replication of JFH1-derived full length genomes was even more sensitive to CypA depletion as compared to subgenomic replicons and virus production was completely blocked. These results argue that CypA may target an additional viral factor outside of the minimal replicase contributing to RNA amplification and assembly, presumably nonstructural protein 2. By selecting for resistance against the cyclosporine analogue DEBIO-025 that targets CypA in a dose-dependent manner, we identified two mutations (V2440A and V2440L) close to the cleavage site between nonstructural protein 5A and the RNA-dependent RNA polymerase in nonstructural protein 5B that slow down cleavage kinetics at this site and reduce CypA dependence of viral replication. Further amino acid substitutions at the same cleavage site accelerating processing increase CypA dependence. Our results thus identify an unexpected correlation between HCV polyprotein processing and CypA dependence of HCV replication.