The Experts below are selected from a list of 267 Experts worldwide ranked by ideXlab platform
Thomas Shenk - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of cyclooxygenase activity blocks cell-to-cell spread of Human Cytomegalovirus
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Jörg Schröer, Thomas ShenkAbstract:Human Cytomegalovirus has previously been shown to induce the accumulation of cyclooxygenase-2 RNA, protein, and enzyme activity. High doses of cyclooxygenase inhibitors substantially block viral replication in cultured fibroblasts. However, doses corresponding to the level of drug achieved in the plasma of patients have little effect on the replication of Human Cytomegalovirus in cultured cells. Here, we demonstrate that two nonsteroidal anti-inflammatory drugs, tolfenamic acid and indomethacin, markedly reduce direct cell-to-cell spread of Human Cytomegalovirus in cultured fibroblasts. The block is reversed by addition of prostaglandin E2, proving that it results from the action of the drugs on cyclooxygenase activity. Because direct cell-to-cell spread likely contributes importantly to pathogenesis of the virus, we suggest that nonsteroidal anti-inflammatory drugs might help to control Human Cytomegalovirus infections in conjunction with other anti-viral treatments.
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Evaluation of the host transcriptional response to Human Cytomegalovirus infection.
Physiological genomics, 2004Co-Authors: Jean F. Challacombe, Thomas Shenk, Andreas Rechtsteiner, Raphael Gottardo, Luis Mateus Rocha, Edward P. Browne, Michael R. Altherr, Thomas BrettinAbstract:Gene expression data from Human Cytomegalovirus (HCMV)-infected cells were analyzed using DNA-Chip Analyzer (dChip) followed by singular value decomposition (SVD) and compared with a previous analy...
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Reevaluation of Human Cytomegalovirus coding potential.
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Eain Murphy, Isidore Rigoutsos, Tetsuo Shibuya, Thomas ShenkAbstract:The Bio-Dictionary-based Gene Finder was used to reassess the coding potential of the AD169 laboratory strain of Human Cytomegalovirus and sequences in the Toledo strain that are missing in the laboratory strain of the virus. The gene-finder algorithm assesses the potential of an ORF to encode a protein based on matches to a database of amino acid patterns derived from a large collection of proteins. The algorithm was used to score all Human Cytomegalovirus ORFs with the potential to encode polypeptides ≥50 aa in length. As a further test for functionality, the genomes of the chimpanzee, rhesus, and murine Cytomegaloviruses were searched for orthologues of the predicted Human Cytomegalovirus ORFs. The analysis indicates that 37 previously annotated ORFs ought to be discarded, and at least nine previously unrecognized ORFs with relatively strong coding potential should be added. Thus, the Human Cytomegalovirus genome appears to contain ≈192 unique ORFs with the potential to encode a protein. Support for several of the predictions of our in silico analysis was obtained by sequencing several domains within a clinical isolate of Human Cytomegalovirus.
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In Silico Pattern-Based Analysis of the Human Cytomegalovirus Genome
Journal of virology, 2003Co-Authors: Isidore Rigoutsos, Jiri Novotny, Tien Huynh, Stephen T. Chin-bow, Laxmi Parida, Daniel E. Platt, David Coleman, Thomas ShenkAbstract:More than 200 open reading frames (ORFs) from the Human Cytomegalovirus genome have been reported as potentially coding for proteins. We have used two pattern-based in silico approaches to analyze this set of putative viral genes. With the help of an objective annotation method that is based on the Bio-Dictionary, a comprehensive collection of amino acid patterns that describes the currently known natural sequence space of proteins, we have reannotated all of the previously reported putative genes of the Human Cytomegalovirus. Also, with the help of MUSCA, a pattern-based multiple sequence alignment algorithm, we have reexamined the original Human Cytomegalovirus gene family definitions. Our analysis of the genome shows that many of the coded proteins comprise amino acid combinations that are unique to either the Human Cytomegalovirus or the larger group of herpesviruses. We have confirmed that a surprisingly large portion of the analyzed ORFs encode membrane proteins, and we have discovered a significant number of previously uncharacterized proteins that are predicted to be G-protein-coupled receptor homologues. The analysis also indicates that many of the encoded proteins undergo posttranslational modifications such as hydroxylation, phosphorylation, and glycosylation. ORFs encoding proteins with similar functional behavior appear in neighboring regions of the Human Cytomegalovirus genome. All of the results of the present study can be found and interactively explored online (http://cbcsrv.watson.ibm.com/virus/).
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Inhibition of cyclooxygenase 2 blocks Human Cytomegalovirus replication.
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Hua Zhu, Jian Ping Cong, Wade A. Bresnahan, Thomas ShenkAbstract:Cyclooxygenase 2 (COX-2) mRNA, protein, and activity are transiently induced after infection of Human fibroblasts with Human Cytomegalovirus. Prostaglandin E2, the product of COX-2 activity, is transiently increased by a factor of >50 in cultures of virus-infected fibroblasts. Both specific (BMS-279652, 279654, and 279655) and nonspecific (indomethacin) COX-2 inhibitors can abrogate the virus-mediated induction of prostaglandin E2 accumulation. Levels of COX-2 inhibitors that completely block the induction of COX-2 activity, but do not compromise cell viability, reduce the yield of Human Cytomegalovirus in Human fibroblasts by a factor of >100. Importantly, the yield of infectious virus can be substantially restored by the addition of prostaglandin E2 together with the inhibitory drug. This finding argues that elevated levels of prostaglandin E2 are required for efficient replication of Human Cytomegalovirus in fibroblasts. COX-2 inhibitors block the accumulation of immediate-early 2 mRNA and protein, but have little effect on the levels of immediate-early 1 mRNA and protein. Viral DNA replication and the accumulation of some, but not all, early and late mRNAs are substantially blocked by COX-2 inhibitors. Elevated levels of prostaglandin E2 apparently facilitate the production of immediate-early 2 protein. The failure to produce normal levels of this critical viral regulatory protein in the presence of COX-2 inhibitors might block normal progression beyond the immediate-early phase of Human Cytomegalovirus infection.
David J. Meyers - One of the best experts on this subject based on the ideXlab platform.
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Validation and Characterization of Five Distinct Novel Inhibitors of Human Cytomegalovirus
Journal of medicinal chemistry, 2020Co-Authors: Arun Kapoor, Ayan Kumar Ghosh, Michael Forman, Noel Southall, Juan J. Marugan, Robert F. Keyes, Brian C. Smith, David J. MeyersAbstract:The critical consequences of Human Cytomegalovirus (HCMV) infection in the transplant population and in congenitally infected infants, the limited treatment options for HCMV, and the rise of resist...
Finn Grey - One of the best experts on this subject based on the ideXlab platform.
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Systematic microRNA analysis identifies ATP6V0C as an essential host factor for Human Cytomegalovirus replication.
PLoS pathogens, 2013Co-Authors: Jonathan Pavelin, Natalie L. Reynolds, Stephen Chiweshe, Rebecca Tiribassi, Finn GreyAbstract:Recent advances in microRNA target identification have greatly increased the number of putative targets of viral microRNAs. However, it is still unclear whether all targets identified are biologically relevant. Here, we use a combined approach of RISC immunoprecipitation and focused siRNA screening to identify targets of HCMV encoded Human Cytomegalovirus that play an important role in the biology of the virus. Using both a laboratory and clinical strain of Human Cytomegalovirus, we identify over 200 putative targets of Human Cytomegalovirus microRNAs following infection of fibroblast cells. By comparing RISC-IP profiles of miRNA knockout viruses, we have resolved specific interactions between Human Cytomegalovirus miRNAs and the top candidate target transcripts and validated regulation by western blot analysis and luciferase assay. Crucially we demonstrate that miRNA target genes play important roles in the biology of Human Cytomegalovirus as siRNA knockdown results in marked effects on virus replication. The most striking phenotype followed knockdown of the top target ATP6V0C, which is required for endosomal acidification. siRNA knockdown of ATP6V0C resulted in almost complete loss of infectious virus production, suggesting that an HCMV microRNA targets a crucial cellular factor required for virus replication. This study greatly increases the number of identified targets of Human Cytomegalovirus microRNAs and demonstrates the effective use of combined miRNA target identification and focused siRNA screening for identifying novel host virus interactions.
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Identification and Characterization of Human Cytomegalovirus-Encoded MicroRNAs
Journal of virology, 2005Co-Authors: Finn Grey, Andy Antoniewicz, Edwards Allen, Julie A. Saugstad, Andy Mcshea, James C. Carrington, Jay A. NelsonAbstract:MicroRNAs (miRNAs) are an extensive class of noncoding genes that regulate gene expression through posttranscriptional repression. Given the potential for large viral genomes to encode these transcripts, we examined the Human Cytomegalovirus AD169 genome for miRNAs using a bioinformatics approach. We identified 406 potential stem-loops, of which 110 were conserved between chimpanzee Cytomegalovirus and several strains of Human Cytomegalovirus. Of these conserved stem-loops, 13 exhibited a significant score using the MiRscan algorithm. Examination of total RNA from Human Cytomegalovirus-infected cells demonstrated that 5 of the 13 predicted miRNAs were expressed during infection. These studies demonstrate that Human Cytomegalovirus encodes multiple conserved miRNAs and suggest that Human Cytomegalovirus may utilize an miRNA strategy to regulate cellular and viral gene function.
Stanley A. Plotkin - One of the best experts on this subject based on the ideXlab platform.
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Preventing Infection by Human Cytomegalovirus.
The Journal of infectious diseases, 2020Co-Authors: Stanley A. PlotkinAbstract:The way to a successful vaccine against Human Cytomegalovirus is hampered by the peculiar biology of this infection. However, some candidate vaccines have been shown to protect seronegative women and transplant recipients, and we should know soon whether they can prevent congenital infection.
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Vaccination against the Human Cytomegalovirus.
Vaccine, 2018Co-Authors: Stanley A. Plotkin, Suresh B. BoppanaAbstract:The Human Cytomegalovirus (HCMV) is the most important infectious cause of congenital abnormalities and also of infectious complications of transplantation. The biology of the infection is complex and acquired immunity does not always prevent reinfection. Nevertheless, vaccine development is far advanced, with numerous candidate vaccines being tested, both live and inactivated. This article summarizes the status of the candidate vaccines.
Susan P Manly - One of the best experts on this subject based on the ideXlab platform.
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Bripiodionen, a new inhibitor of Human Cytomegalovirus protease from Streptomyces sp. WC76599
Journal of Natural Products, 1997Co-Authors: Yue Zhong Shu, Janet M. Kolb, Stella Huang, Qingmei Ye, Jennifer A Veitch, Susan E. Lowe, Susan P ManlyAbstract:Bripiodionen (1), a new natural product, was isolated from Streptomyces sp. WC76599 during the screening of microbial fermentation extracts for their ability to inhibit Human Cytomegalovirus protease. The structure of 1 was elucidated by spectroscopic methods. Compound 1 displayed inhibitory activity against Human Cytomegalovirus protease with an IC50 value of 30 microM.
