Artykuły w czasopismach: „Cytomegaloviruses”

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Flores-Martínez, Yulia Alejandra, Vu Thuy Khanh Le-Trilling i Mirko Trilling. "Nedd8-Activating Enzyme Is a Druggable Host Dependency Factor of Human and Mouse Cytomegalovirus". Viruses 13, nr 8 (14.08.2021): 1610. http://dx.doi.org/10.3390/v13081610.

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Human cytomegalovirus causes diseases in individuals with insufficient immunity. Cytomegaloviruses exploit the ubiquitin proteasome pathway to manipulate the proteome of infected cells. The proteasome degrades ubiquitinated proteins. The family of cullin RING ubiquitin ligases (CRL) regulates the stability of numerous important proteins. If the cullin within the CRL is modified with Nedd8 (“neddylated”), the CRL is enzymatically active, while CRLs lacking Nedd8 modifications are inactive. The Nedd8-activating enzyme (NAE) is indispensable for neddylation. By binding to NAE and inhibiting neddylation, the drug MLN4924 (pevonedistat) causes CRL inactivation and stabilization of CRL target proteins. We showed that MLN4924 elicits potent antiviral activity against cytomegaloviruses, suggesting that NAE might be a druggable host dependency factor (HDF). However, MLN4924 is a nucleoside analog related to AMP, and the antiviral activity of MLN4924 may have been influenced by off-target effects in addition to NAE inhibition. To test if NAE is indeed an HDF, we assessed the novel NAE inhibitor TAS4464 and observed potent antiviral activity against mouse and human cytomegalovirus. Additionally, we raised an MLN4924-resistant cell clone and showed that MLN4924 as well as TAS4464 lose their antiviral activity in these cells. Our results indicate that NAE, the neddylation process, and CRLs are druggable HDFs of cytomegaloviruses.

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Khan, Taimoor, Abbas Khan, Syed Nouman Nasir, Sajjad Ahmad, Syed Shujait Ali i Dong-Qing Wei. "CytomegaloVirusDb: Multi-omics knowledge database for cytomegaloviruses". Computers in Biology and Medicine 135 (sierpień 2021): 104563. http://dx.doi.org/10.1016/j.compbiomed.2021.104563.

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McCormick, A. Louise, Christopher D. Meiering, Geoffrey B. Smith i Edward S. Mocarski. "Mitochondrial Cell Death Suppressors Carried by Human and Murine Cytomegalovirus Confer Resistance to Proteasome Inhibitor-Induced Apoptosis". Journal of Virology 79, nr 19 (1.10.2005): 12205–17. http://dx.doi.org/10.1128/jvi.79.19.12205-12217.2005.

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ABSTRACT Human cytomegalovirus carries a mitochondria-localized inhibitor of apoptosis (vMIA) that is conserved in primate cytomegaloviruses. We find that inactivating mutations within UL37x1, which encodes vMIA, do not substantially affect replication in TownevarATCC (Towne-BAC), a virus that carries a functional copy of the betaherpesvirus-conserved viral inhibitor of caspase 8 activation, the UL36 gene product. In Towne-BAC infection, vMIA reduces susceptibility of infected cells to intrinsic death induced by proteasome inhibition. vMIA is sufficient to confer resistance to proteasome inhibition when expressed independent of viral infection. Murine cytomegalovirus m38.5, whose position in the viral genome is analogous to UL37x1, exhibits mitochondrial association and functions in much the same manner as vMIA in inhibiting intrinsic cell death. This work suggests a common role for vMIA in rodent and primate cytomegaloviruses, modulating the threshold of virus-infected cells to intrinsic cell death.

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Staczek, J. "Animal cytomegaloviruses." Microbiological Reviews 54, nr 3 (1990): 247–65. http://dx.doi.org/10.1128/mmbr.54.3.247-265.1990.

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Staczek, J. "Animal cytomegaloviruses." Microbiological Reviews 54, nr 3 (1990): 247–65. http://dx.doi.org/10.1128/mr.54.3.247-265.1990.

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Bahr, Udo, i Gholamreza Darai. "Analysis and Characterization of the Complete Genome of Tupaia (Tree Shrew) Herpesvirus". Journal of Virology 75, nr 10 (15.05.2001): 4854–70. http://dx.doi.org/10.1128/jvi.75.10.4854-4870.2001.

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ABSTRACT The tupaia herpesvirus (THV) was isolated from spontaneously degenerating tissue cultures of malignant lymphoma, lung, and spleen cell cultures of tree shrews (Tupaia spp.). The determination of the complete nucleotide sequence of the THV strain 2 genome resulted in a 195,857-bp-long, linear DNA molecule with a G+C content of 66.5%. The terminal regions of the THV genome and the loci of conserved viral genes were found to be G+C richer. Furthermore, no large repetitive DNA sequences could be identified. This is in agreement with the previous classification of THV as the prototype species of herpesvirus genome group F. The search for potential coding regions resulted in the identification of 158 open reading frames (ORFs) regularly distributed on both DNA strands. Seventy-six out of the 158 ORFs code for proteins that are significantly homologous to known herpesvirus proteins. The highest homologies found were to primate and rodent cytomegaloviruses. Biological properties, protein homologies, the arrangement of conserved viral genes, and phylogenetic analysis revealed that THV is a member of the subfamilyBetaherpesvirinae. The evolutionary lineages of THV and the cytomegaloviruses seem to have branched off from a common ancestor. In addition, it was found that the arrangements of conserved genes of THV and murine cytomegalovirus strain Smith, both of which are not able to form genomic isomers, are colinear with two different human cytomegalovirus (HCMV) strain AD169 genomic isomers that differ from each other in the orientation of the long unique region. The biological properties and the high degree of relatedness of THV to the mammalian cytomegaloviruses allow the consideration of THV as a model system for investigation of HCMV pathogenicity.

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Becker, Tanja, Vu Le-Trilling i Mirko Trilling. "Cellular Cullin RING Ubiquitin Ligases: Druggable Host Dependency Factors of Cytomegaloviruses". International Journal of Molecular Sciences 20, nr 7 (2.04.2019): 1636. http://dx.doi.org/10.3390/ijms20071636.

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Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that frequently causes morbidity and mortality in individuals with insufficient immunity, such as transplant recipients, AIDS patients, and congenitally infected newborns. Several antiviral drugs are approved to treat HCMV infections. However, resistant HCMV mutants can arise in patients receiving long-term therapy. Additionally, side effects and the risk to cause birth defects limit the use of currently approved antivirals against HCMV. Therefore, the identification of new drug targets is of clinical relevance. Recent work identified DNA-damage binding protein 1 (DDB1) and the family of the cellular cullin (Cul) RING ubiquitin (Ub) ligases (CRLs) as host-derived factors that are relevant for the replication of human and mouse cytomegaloviruses. The first-in-class CRL inhibitory compound Pevonedistat (also called MLN4924) is currently under investigation as an anti-tumor drug in several clinical trials. Cytomegaloviruses exploit CRLs to regulate the abundance of viral proteins, and to induce the proteasomal degradation of host restriction factors involved in innate and intrinsic immunity. Accordingly, pharmacological blockade of CRL activity diminishes viral replication in cell culture. In this review, we summarize the current knowledge concerning the relevance of DDB1 and CRLs during cytomegalovirus replication and discuss chances and drawbacks of CRL inhibitory drugs as potential antiviral treatment against HCMV.

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Forrest, Calum, Ariane Gomes, Matthew Reeves i Victoria Male. "NK Cell Memory to Cytomegalovirus: Implications for Vaccine Development". Vaccines 8, nr 3 (20.07.2020): 394. http://dx.doi.org/10.3390/vaccines8030394.

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Natural killer (NK) cells are innate lymphoid cells that recognize and eliminate virally-infected and cancerous cells. Members of the innate immune system are not usually considered to mediate immune memory, but over the past decade evidence has emerged that NK cells can do this in several contexts. Of these, the best understood and most widely accepted is the response to cytomegaloviruses, with strong evidence for memory to murine cytomegalovirus (MCMV) and several lines of evidence suggesting that the same is likely to be true of human cytomegalovirus (HCMV). The importance of NK cells in the context of HCMV infection is underscored by the armory of NK immune evasion genes encoded by HCMV aimed at subverting the NK cell immune response. As such, ongoing studies that have utilized HCMV to investigate NK cell diversity and function have proven instructive. Here, we discuss our current understanding of NK cell memory to viral infection with a focus on the response to cytomegaloviruses. We will then discuss the implications that this will have for the development of a vaccine against HCMV with particular emphasis on how a strategy that can harness the innate immune system and NK cells could be crucial for the development of a vaccine against this high-priority pathogen.

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Marschall, Manfred, Thomas Stamminger, Andreas Urban, Steffen Wildum, Helga Ruebsamen-Schaeff, Holger Zimmermann i Peter Lischka. "In VitroEvaluation of the Activities of the Novel Anticytomegalovirus Compound AIC246 (Letermovir) against Herpesviruses and Other Human Pathogenic Viruses". Antimicrobial Agents and Chemotherapy 56, nr 2 (21.11.2011): 1135–37. http://dx.doi.org/10.1128/aac.05908-11.

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ABSTRACTAIC246 (letermovir) is a potent anticytomegalovirus drug in clinical development. Here, we report a consistent antiviral efficacy of AIC246 against human cytomegalovirus laboratory strains, clinical isolates, and virus variants resistant to approved drugs. Furthermore, we describe a remarkable selectivity of AIC246 for human cytomegaloviruses compared to that of other alpha-, beta-, or gammaherpesviruses or nonrelated pathogenic viruses, including adeno-, hepadna-, retro-, orthomyxo-, and flaviviruses. Our data confirm and support an excellent and selective anticytomegaloviral activity of AIC246.

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Bierle, Craig J., Kaitlyn M. Anderholm, Jian Ben Wang, Michael A. McVoy i Mark R. Schleiss. "Targeted Mutagenesis of Guinea Pig Cytomegalovirus Using CRISPR/Cas9-Mediated Gene Editing". Journal of Virology 90, nr 15 (25.05.2016): 6989–98. http://dx.doi.org/10.1128/jvi.00139-16.

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ABSTRACTThe cytomegaloviruses (CMVs) are among the most genetically complex mammalian viruses, with viral genomes that often exceed 230 kbp. Manipulation of cytomegalovirus genomes is largely performed using infectious bacterial artificial chromosomes (BACs), which necessitates the maintenance of the viral genome inEscherichia coliand successful reconstitution of virus from permissive cells after transfection of the BAC. Here we describe an alternative strategy for the mutagenesis of guinea pig cytomegalovirus that utilizes clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated genome editing to introduce targeted mutations to the viral genome. Transient transfection and drug selection were used to restrict lytic replication of guinea pig cytomegalovirus to cells that express Cas9 and virus-specific guide RNA. The result was highly efficient editing of the viral genome that introduced targeted insertion or deletion mutations to nonessential viral genes. Cotransfection of multiple virus-specific guide RNAs or a homology repair template was used for targeted, markerless deletions of viral sequence or to introduce exogenous sequence by homology-driven repair. As CRISPR/Cas9 mutagenesis occurs directly in infected cells, this methodology avoids selective pressures that may occur during propagation of the viral genome in bacteria and may facilitate genetic manipulation of low-passage or clinical CMV isolates.IMPORTANCEThe cytomegalovirus genome is complex, and viral adaptations to cell culture have complicated the study of infectionin vivo. Recombineering of viral bacterial artificial chromosomes enabled the study of recombinant cytomegaloviruses. Here we report the development of an alternative approach using CRISPR/Cas9-based mutagenesis in guinea pig cytomegalovirus, a small-animal model of congenital cytomegalovirus disease. CRISPR/Cas9 mutagenesis can introduce the same types of mutations to the viral genome as bacterial artificial chromosome recombineering but does so directly in virus-infected cells. CRISPR/Cas9 mutagenesis is not dependent on a bacterial intermediate, and defined viral mutants can be recovered after a limited number of viral genome replications, minimizing the risk of spontaneous mutation.

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Vink, Cornelis, Patrick S. Beisser i Cathrien A. Bruggeman. "Molecular Mimicry by Cytomegaloviruses". Intervirology 42, nr 5-6 (1999): 342–49. http://dx.doi.org/10.1159/000053970.

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Spoden, Gilles A., Katrin Besold, Steffi Krauter, Bodo Plachter, Nils Hanik, Andreas F. M. Kilbinger, Carsten Lambert i Luise Florin. "Polyethylenimine Is a Strong Inhibitor of Human Papillomavirus and Cytomegalovirus Infection". Antimicrobial Agents and Chemotherapy 56, nr 1 (3.10.2011): 75–82. http://dx.doi.org/10.1128/aac.05147-11.

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ABSTRACTPolyethylenimines are cationic polymers with potential as delivery vectors in gene therapy and with proven antimicrobial activity. However, the antiviral activity of polyethylenimines has not been addressed in detail thus far. We have studied the inhibitory effects of a linear 25-kDa polyethylenimine on infections with human papillomaviruses and human cytomegaloviruses. Preincubation of cells with polyethylenimine blocked primary attachment of both viruses to cells, resulting in a significant reduction of infection. In addition, the dissemination of human cytomegalovirus in culture cells was efficiently reduced by recurrent administration of polyethylenimine. Polyethylenimine concentrations required for inhibition of human papillomavirus and cytomegalovirus did not cause any cytotoxic effects. Polyethylenimines and their derivatives may thus be attractive molecules for the development of antiviral microbicides.

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Schumacher, Uwe, Wiebke Handke, Igor Jurak i Wolfram Brune. "Mutations in the M112/M113-Coding Region Facilitate Murine Cytomegalovirus Replication in Human Cells". Journal of Virology 84, nr 16 (2.06.2010): 7994–8006. http://dx.doi.org/10.1128/jvi.02624-09.

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ABSTRACT Cytomegaloviruses, representatives of the Betaherpesvirinae, cause opportunistic infections in immunocompromised hosts. They infect various cells and tissues in their natural host but are highly species specific. For instance, human cytomegalovirus (HCMV) does not replicate in mouse cells, and human cells are not permissive for murine cytomegalovirus (MCMV) infection. However, the underlying molecular mechanisms are so far poorly understood. In the present study we isolated and characterized a spontaneously occurring MCMV mutant that has gained the capacity to replicate rapidly and to high titers in human cells. Compared to the parental wild-type (wt) virus, this mutant formed larger nuclear replication compartments and replicated viral DNA more efficiently. It also disrupted promyelocytic leukemia (PML) protein nuclear domains with greater efficiency but caused less apoptosis than did wt MCMV. Sequence analysis of the mutant virus genome revealed mutations in the M112/M113-coding region. This region is homologous to the HCMV UL112-113 region and encodes the viral early 1 (E1) proteins, which are known to play an important role in viral DNA replication. By introducing the M112/M113 mutations into wt MCMV, we demonstrated that they are sufficient to facilitate MCMV replication in human cells and are, at least in part, responsible for the efficient replication capability of the spontaneously adapted virus. However, additional mutations probably contribute as well. These results reveal a previously unrecognized role of the viral E1 proteins in regulating viral replication in different cells and provide new insights into the mechanisms of the species specificity of cytomegaloviruses.

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Smith, L. M., J. N. Tonkin, M. A. Lawson i G. R. Shellam. "Isolates of cytomegalovirus (CMV) from the black rat Rattus rattus form a distinct group of rat CMV". Journal of General Virology 85, nr 5 (1.05.2004): 1313–17. http://dx.doi.org/10.1099/vir.0.79839-0.

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Two different betaherpesviruses, the English and Maastricht species of rat cytomegalovirus (CMV), have previously been isolated from Rattus norvegicus. CMVs were isolated from both the brown rat, R. norvegicus, and the black rat, R. rattus, within Australia. The viruses isolated from R. norvegicus appeared to be genetically related to the English species of rat CMV by PCR, RFLP, and sequencing, but the viruses isolated from R. rattus were distinct from both prototype virus species, although more closely genetically related to the Maastricht virus. This is the first genetic characterization of cytomegaloviruses from R. rattus, and the first isolation of CMVs from Australian rats.

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Cagliani, Rachele, Diego Forni, Alessandra Mozzi i Manuela Sironi. "Evolution and Genetic Diversity of Primate Cytomegaloviruses". Microorganisms 8, nr 5 (25.04.2020): 624. http://dx.doi.org/10.3390/microorganisms8050624.

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Cytomegaloviruses (CMVs) infect many mammals, including humans and non–human primates (NHPs). Human cytomegalovirus (HCMV) is an important opportunistic pathogen among immunocompromised patients and represents the most common infectious cause of birth defects. HCMV possesses a large genome and very high genetic diversity. NHP–infecting CMVs share with HCMV a similar genomic organization and coding content, as well as the course of viral infection. Recent technological advances have allowed the sequencing of several HCMV strains from clinical samples and provided insight into the diversity of NHP–infecting CMVs. The emerging picture indicates that, with the exclusion of core genes (genes that have orthologs in all herpesviruses), CMV genomes are relatively plastic and diverse in terms of gene content, both at the inter– and at the intra–species level. Such variability most likely underlies the strict species–specificity of these viruses, as well as their ability to persist lifelong and with relatively little damage to their hosts. However, core genes, despite their strong conservation, also represented a target of adaptive evolution and subtle changes in their coding sequence contributed to CMV adaptation to different hosts. Indubitably, important knowledge gaps remain, the most relevant of which concerns the role of viral genetics in HCMV–associated human disease.

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Hill, Ann. "Cytomegaloviruses: Molecular Biology and Immunology". Expert Review of Anti-infective Therapy 4, nr 4 (sierpień 2006): 563–64. http://dx.doi.org/10.1586/14787210.4.4.563.

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Lisnić, Berislav, Vanda Juranić Lisnić i Stipan Jonjić. "NK cell interplay with cytomegaloviruses". Current Opinion in Virology 15 (grudzień 2015): 9–18. http://dx.doi.org/10.1016/j.coviro.2015.07.001.

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Reddehase, Matthias J., i Niels A. W. Lemmermann. "Cellular reservoirs of latent cytomegaloviruses". Medical Microbiology and Immunology 208, nr 3-4 (22.04.2019): 391–403. http://dx.doi.org/10.1007/s00430-019-00592-y.

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Goldmacher, V. S. "Cell death suppression by cytomegaloviruses". Apoptosis 10, nr 2 (marzec 2005): 251–65. http://dx.doi.org/10.1007/s10495-005-0800-z.

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Hancock, Trevor J., Morgan Lynn Hetzel, Andrea Ramirez i Tim E. Sparer. "MCMV Centrifugal Enhancement: A New Spin on an Old Topic". Pathogens 10, nr 12 (3.12.2021): 1577. http://dx.doi.org/10.3390/pathogens10121577.

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Human cytomegalovirus (HCMV) is a ubiquitous pathogen infecting a majority of people worldwide, with diseases ranging from mild to life-threatening. Its clinical relevance in immunocompromised people and congenital infections have made treatment and vaccine development a top priority. Because of cytomegaloviruses’ species specificity, murine cytomegalovirus (MCMV) models have historically informed and advanced translational CMV therapies. Using the phenomenon of centrifugal enhancement, we explored differences between MCMVs derived in vitro and in vivo. We found centrifugal enhancement on tissue culture-derived virus (TCV) was ~3× greater compared with salivary gland derived virus (SGV). Using novel “flow virometry”, we found that TCV contained a distinct submicron particle composition compared to SGV. Using an inhibitor of exosome production, we show these submicron particles are not extracellular vesicles that contribute to centrifugal enhancement. We examined how these differences in submicron particles potentially contribute to differing centrifugal enhancement phenotypes, as well as broader in vivo vs. in vitro MCMV differences.

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Brocchieri, Luciano, Thomas N. Kledal, Samuel Karlin i Edward S. Mocarski. "Predicting Coding Potential from Genome Sequence: Application to Betaherpesviruses Infecting Rats and Mice". Journal of Virology 79, nr 12 (15.06.2005): 7570–96. http://dx.doi.org/10.1128/jvi.79.12.7570-7596.2005.

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ABSTRACT Prediction of protein-coding regions and other features of primary DNA sequence have greatly contributed to experimental biology. Significant challenges remain in genome annotation methods, including the identification of small or overlapping genes and the assessment of mRNA splicing or unconventional translation signals in expression. We have employed a combined analysis of compositional biases and conservation together with frame-specific G+C representation to reevaluate and annotate the genome sequences of mouse and rat cytomegaloviruses. Our analysis predicts that there are at least 34 protein-coding regions in these genomes that were not apparent in earlier annotation efforts. These include 17 single-exon genes, three new exons of previously identified genes, a newly identified four-exon gene for a lectin-like protein (in rat cytomegalovirus), and 10 probable frameshift extensions of previously annotated genes. This expanded set of candidate genes provides an additional basis for investigation in cytomegalovirus biology and pathogenesis.

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Tang, Julian. "Cytomegaloviruses: From Molecular Pathogenesis to Intervention". Emerging Infectious Diseases 19, nr 11 (listopad 2013): 1906. http://dx.doi.org/10.3201/eid1911.131226.

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Tang, Julian. "Cytomegaloviruses: From Molecular Pathogenesis to Intervention". Emerging Infectious Diseases 19, nr 11 (listopad 2013): 1906. http://dx.doi.org/10.3201/eis1911.131226.

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Fliss, Patricia M., i Wolfram Brune. "Prevention of Cellular Suicide by Cytomegaloviruses". Viruses 4, nr 10 (2.10.2012): 1928–49. http://dx.doi.org/10.3390/v4101928.

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Kavanagh, Daniel G., Marielle C. Gold, Markus Wagner, Ulrich H. Koszinowski i Ann B. Hill. "The Multiple Immune-Evasion Genes of Murine Cytomegalovirus Are Not Redundant". Journal of Experimental Medicine 194, nr 7 (1.10.2001): 967–78. http://dx.doi.org/10.1084/jem.194.7.967.

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Both human cytomegaloviruses (HCMVs) and murine cytomegaloviruses (MCMVs) encode multiple genes that interfere with antigen presentation by major histocompatibility complex (MHC) class I, and thus protect infected targets from lysis by virus-specific cytotoxic T lymphocytes (CTLs). HCMV has been shown to encode four such genes and MCMV to encode two. MCMV m152 blocks the export of class I from a pre-Golgi compartment, and MCMV m6 directs class I to the lysosome for degradation. A third MCMV gene, m4, encodes a glycoprotein which is expressed at the cell surface in association with class I. Here we here show that m4 is a CTL-evasion gene which, unlike previously described immune-evasion genes, inhibited CTLs without blocking class I surface expression. m152 was necessary to block antigen presentation to both Kb- and Db-restricted CTL clones, while m4 was necessary to block presentation only to Kb-restricted clones. m152 caused complete retention of Db, but only partial retention of Kb, in a pre-Golgi compartment. Thus, while m152 effectively inhibited Db-restricted CTLs, m4 was required to completely inhibit Kb-restricted CTLs. We propose that cytomegaloviruses encode multiple immune-evasion genes in order to cope with the diversity of class I molecules in outbred host populations.

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Krstanović, Fran, William J. Britt, Stipan Jonjić i Ilija Brizić. "Cytomegalovirus Infection and Inflammation in Developing Brain". Viruses 13, nr 6 (4.06.2021): 1078. http://dx.doi.org/10.3390/v13061078.

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Human cytomegalovirus (HCMV) is a highly prevalent herpesvirus that can cause severe disease in immunocompromised individuals and immunologically immature fetuses and newborns. Most infected newborns are able to resolve the infection without developing sequelae. However, in severe cases, congenital HCMV infection can result in life-threatening pathologies and permanent damage of organ systems that possess a low regenerative capacity. Despite the severity of the problem, HCMV infection of the central nervous system (CNS) remains inadequately characterized to date. Cytomegaloviruses (CMVs) show strict species specificity, limiting the use of HCMV in experimental animals. Infection following intraperitoneal administration of mouse cytomegalovirus (MCMV) into newborn mice efficiently recapitulates many aspects of congenital HCMV infection in CNS. Upon entering the CNS, CMV targets all resident brain cells, consequently leading to the development of widespread histopathology and inflammation. Effector functions from both resident cells and infiltrating immune cells efficiently resolve acute MCMV infection in the CNS. However, host-mediated inflammatory factors can also mediate the development of immunopathologies during CMV infection of the brain. Here, we provide an overview of the cytomegalovirus infection in the brain, local immune response to infection, and mechanisms leading to CNS sequelae.

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Fukui, Yoshiko, Keiko Shindoh, Yumiko Yamamoto, Shin Koyano, Isao Kosugi, Toyofumi Yamaguchi, Ichiro Kurane i Naoki Inoue. "Establishment of a Cell-Based Assay for Screening of Compounds Inhibiting Very Early Events in the Cytomegalovirus Replication Cycle and Characterization of a Compound Identified Using the Assay". Antimicrobial Agents and Chemotherapy 52, nr 7 (5.05.2008): 2420–27. http://dx.doi.org/10.1128/aac.00134-08.

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ABSTRACT To simplify the detection of infectious human cytomegalovirus (HCMV), we generated a cell line that produced luciferase in a dose-dependent manner upon HCMV infection. Using this cell line, we identified anti-HCMV compounds from a diverse library of 9,600 compounds. One of them, 1-(3,5-dichloro-4-pyridyl)piperidine-4-carboxamide (DPPC), was effective against HCMV (Towne strain) infection of human lung fibroblast cells at a 50% effective concentration of 2.5 μM. DPPC also inhibited the growth of clinical HCMV isolates and guinea pig and mouse cytomegaloviruses. Experiments using various time frames for treatment of the cells with DPPC demonstrated that DPPC was effective during the first 24 h after HCMV infection. DPPC treatment decreased not only viral DNA replication but also IE1 and IE2 expression at mRNA and protein levels in the HCMV-infected cells. However, DPPC did not inhibit the attachment of HCMV particles to the cell surface. DPPC is a unique compound that targets the very early phase of cytomegalovirus infection, probably by disrupting a pathway that is important after viral entry but before immediate-early gene expression.

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Revilleza, Maria Jamela, Rui Wang, Janet Mans, Manqing Hong, Kannan Natarajan i David H. Margulies. "How the Virus Outsmarts the Host: Function and Structure of Cytomegalovirus MHC-I-Like Molecules in the Evasion of Natural Killer Cell Surveillance". Journal of Biomedicine and Biotechnology 2011 (2011): 1–12. http://dx.doi.org/10.1155/2011/724607.

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Natural killer (NK) cells provide an initial host immune response to infection by many viral pathogens. Consequently, the viruses have evolved mechanisms to attenuate the host response, leading to improved viral fitness. One mechanism employed by members of theβ-herpesvirus family, which includes the cytomegaloviruses, is to modulate the expression of cell surface ligands recognized by NK cell activation molecules. A novel set of cytomegalovirus (CMV) genes, exemplified by the mouse m145 family, encode molecules that have structural and functional features similar to those of host major histocompatibility-encoded (MHC) class I molecules, some of which are known to contribute to immune evasion. In this review, we explore the function, structure, and evolution of MHC-I-like molecules of the CMVs and speculate on the dynamic development of novel immunoevasive functions based on the MHC-I protein fold.

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Ynga-Durand, Dekhtiarenko i Cicin-Sain. "Vaccine Vectors Harnessing the Power of Cytomegaloviruses". Vaccines 7, nr 4 (17.10.2019): 152. http://dx.doi.org/10.3390/vaccines7040152.

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Cytomegalovirus (CMV) species have been gaining attention as experimental vaccine vectors inducing cellular immune responses of unparalleled strength and protection. This review outline the strengths and the restrictions of CMV-based vectors, in light of the known aspects of CMV infection, pathogenicity and immunity. We discuss aspects to be considered when optimizing CMV based vaccines, including the innate immune response, the adaptive humoral immunity and the T-cell responses. We also discuss the antigenic epitopes presented by unconventional major histocompatibility complex (MHC) molecules in some CMV delivery systems and considerations about routes for delivery for the induction of systemic or mucosal immune responses. With the first clinical trials initiating, CMV-based vaccine vectors are entering a mature phase of development. This impetus needs to be maintained by scientific advances that feed the progress of this technological platform.

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Brune, Wolfram. "Inhibition of programmed cell death by cytomegaloviruses". Virus Research 157, nr 2 (maj 2011): 144–50. http://dx.doi.org/10.1016/j.virusres.2010.10.012.

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Mocarski, Edward S. "Immunomodulation by cytomegaloviruses: manipulative strategies beyond evasion". Trends in Microbiology 10, nr 7 (lipiec 2002): 332–39. http://dx.doi.org/10.1016/s0966-842x(02)02393-4.

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Reddehase, Matthias J. "The immunogenicity of human and murine cytomegaloviruses". Current Opinion in Immunology 12, nr 4 (sierpień 2000): 390–96. http://dx.doi.org/10.1016/s0952-7915(00)00106-0.

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Reddehase, Matthias J. "The immunogenicity of human and murine cytomegaloviruses". Current Opinion in Immunology 12, nr 6 (grudzień 2000): 738. http://dx.doi.org/10.1016/s0952-7915(00)00171-0.

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Giraldo-Isaza, Maria A., David Jaspan i Arnold W. Cohen. "Postpartum Endometritis Caused by Herpes and Cytomegaloviruses". Obstetrics & Gynecology 117, nr 2, Part 2 (luty 2011): 466–67. http://dx.doi.org/10.1097/aog.0b013e3181f73805.

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Davison, Andrew J., Parvis Akter, Charles Cunningham, Aidan Dolan, Clare Addison, Derrick J. Dargan, Aycan F. Hassan-Walker, Vincent C. Emery, Paul D. Griffiths i Gavin W. G. Wilkinson. "Homology between the human cytomegalovirus RL11 gene family and human adenovirus E3 genes". Journal of General Virology 84, nr 3 (1.03.2003): 657–63. http://dx.doi.org/10.1099/vir.0.18856-0.

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A significant proportion of the human cytomegalovirus (HCMV) genome comprises 12 multigene families that probably arose by gene duplication. One, the RL11 family, contains 12 members, most of which are predicted to encode membrane glycoproteins. Comparisons of sequences near the left end of the genome in several HCMV strains revealed two adjacent open reading frames that potentially encode related proteins: RL6, which is hypervariable, and RL5A, which has not been recognized previously. These genes potentially encode a domain that is the hallmark of proteins encoded by the RL11 family, and thus constitute two new members. A homologous domain is also present in a subset of human adenovirus E3 membrane glycoproteins. Evolution of genes specifying the shared domain in cytomegaloviruses and adenoviruses is characterized by extensive divergence, gene duplication and selective sequence loss. These features prompt speculation about the roles of these genes in the two virus families.

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36

Bakkari, Mohammed Ali. "Targeted Protein-Specific Multi-Epitope-Based Vaccine Designing against Human Cytomegalovirus by Using Immunoinformatics Approaches". Vaccines 11, nr 2 (17.01.2023): 203. http://dx.doi.org/10.3390/vaccines11020203.

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Cytomegaloviruses are emerging pathogenic agents known to cause congenital disorders in humans. In this study, immune epitopes (CTL, B cell and HTL) were screened for highly antigenic target proteins of the Human Cytomegalovirus. These shortlisted epitopes were then joined together through suitable linkers to construct multi epitope-based vaccine constructs (MEVCs). The functionality of each vaccine construct was evaluated through tertiary vaccine structure modelling and validations. Furthermore, physio-chemical properties including allergenicity, antigenicity molecular weight and many others were also predicted. The vaccine designs were also docked with the human TLR-4 receptor to demonstrate the receptor specific affinity and formed interactions. The vaccine peptides sequences were also subjected to codon optimization to confirm the potential vaccines expression in E. coli hosts. Additionally, all the MEVCs were also evaluated for immune response (IgG and IgM) induction. However, further in vivo tests are needed to ensure the efficacy of these vaccine designs.

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Protsenko, A. S., N. V. Avramenko, O. V. Strelko, G. P. Khodak i V. N. Protsenko. "The role of cytomegaloviral infection in young females with ovarian resistance". Journal of obstetrics and women's diseases 54, nr 5S (15.11.2005): 99–100. http://dx.doi.org/10.17816/jowd87603.

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Introduction. The study is aimed at the evaluation of the effects of cytomegaloviruses (CMV) on the development of ovarian resistance (OR) and at the development of a package of diagnostic and therapeutic measures in patients with such pathology.

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Kropp, Kai A., Christian O. Simon, Annette Fink, Angélique Renzaho, Birgit Kühnapfel, Jürgen Podlech, Matthias J. Reddehase i Natascha K. A. Grzimek. "Synergism between the components of the bipartite major immediate-early transcriptional enhancer of murine cytomegalovirus does not accelerate virus replication in cell culture and host tissues". Journal of General Virology 90, nr 10 (1.10.2009): 2395–401. http://dx.doi.org/10.1099/vir.0.012245-0.

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Major immediate-early (MIE) transcriptional enhancers of cytomegaloviruses are key regulators that are regarded as determinants of virus replicative fitness and pathogenicity. The MIE locus of murine cytomegalovirus (mCMV) shows bidirectional gene-pair architecture, with a bipartite enhancer flanked by divergent core promoters. Here, we have constructed recombinant viruses mCMV-ΔEnh1 and mCMV-ΔEnh2 to study the impact of either enhancer component on bidirectional MIE gene transcription and on virus replication in cell culture and various host tissues that are relevant to CMV disease. The data revealed that the two unipartite enhancers can operate independently, but synergize in enhancing MIE gene expression early after infection. Kick-start transcription facilitated by the bipartite enhancer configuration, however, did not ultimately result in accelerated virus replication. We conclude that virus replication, once triggered, proceeds with a fixed speed and we propose that synergism between the components of the bipartite enhancer may rather increase the probability for transcription initiation.

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Mocarski, Edward S., i George W. Kemble. "Recombinant Cytomegaloviruses for Study of Replication and Pathogenesis". Intervirology 39, nr 5-6 (1996): 320–30. http://dx.doi.org/10.1159/000150503.

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Garrett, A. J., i D. E. Warren. "A simple technique for endonuclease mapping of cytomegaloviruses". Journal of Virological Methods 10, nr 3 (marzec 1985): 187–94. http://dx.doi.org/10.1016/0166-0934(85)90059-x.

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Berry, Richard, Gabrielle M. Watson, Stipan Jonjic, Mariapia A. Degli-Esposti i Jamie Rossjohn. "Modulation of innate and adaptive immunity by cytomegaloviruses". Nature Reviews Immunology 20, nr 2 (30.10.2019): 113–27. http://dx.doi.org/10.1038/s41577-019-0225-5.

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Becker, Sara, Annette Fink, Jürgen Podlech, Matthias J. Reddehase i Niels A. Lemmermann. "Host-Adapted Gene Families Involved in Murine Cytomegalovirus Immune Evasion". Viruses 14, nr 1 (11.01.2022): 128. http://dx.doi.org/10.3390/v14010128.

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Cytomegaloviruses (CMVs) are host species-specific and have adapted to their respective mammalian hosts during co-evolution. Host-adaptation is reflected by “private genes” that have specialized in mediating virus-host interplay and have no sequence homologs in other CMV species, although biological convergence has led to analogous protein functions. They are mostly organized in gene families evolved by gene duplications and subsequent mutations. The host immune response to infection, both the innate and the adaptive immune response, is a driver of viral evolution, resulting in the acquisition of viral immune evasion proteins encoded by private gene families. As the analysis of the medically relevant human cytomegalovirus by clinical investigation in the infected human host cannot make use of designed virus and host mutagenesis, the mouse model based on murine cytomegalovirus (mCMV) has become a versatile animal model to study basic principles of in vivo virus-host interplay. Focusing on the immune evasion of the adaptive immune response by CD8+ T cells, we review here what is known about proteins of two private gene families of mCMV, the m02 and the m145 families, specifically the role of m04, m06, and m152 in viral antigen presentation during acute and latent infection.

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Valchanova, Ralitsa S., Marcus Picard-Maureau, Matthias Budt i Wolfram Brune. "Murine Cytomegalovirus m142 and m143 Are both Required To Block Protein Kinase R-Mediated Shutdown of Protein Synthesis". Journal of Virology 80, nr 20 (15.10.2006): 10181–90. http://dx.doi.org/10.1128/jvi.00908-06.

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ABSTRACT Cytomegaloviruses carry the US22 family of genes, which have common sequence motifs but diverse functions. Only two of the 12 US22 family genes of murine cytomegalovirus (MCMV) are essential for virus replication, but their functions have remained unknown. In the present study, we deleted the essential US22 family genes, m142 and m143, from the MCMV genome and propagated the mutant viruses on complementing cells. The m142 and the m143 deletion mutants were both unable to replicate in noncomplementing cells at low and high multiplicities of infection. In cells infected with the deletion mutants, viral immediate-early and early proteins were expressed, but viral DNA replication and synthesis of the late-gene product glycoprotein B were inhibited, even though mRNAs of late genes were present. Global protein synthesis was impaired in these cells, which correlated with phosphorylation of the double-stranded RNA-dependent protein kinase R (PKR) and its target protein, the eukaryotic translation initiation factor 2α, suggesting that m142 and m143 are necessary to block the PKR-mediated shutdown of protein synthesis. Replication of the m142 and m143 knockout mutants was partially restored by expression of the human cytomegalovirus TRS1 gene, a known double-stranded-RNA-binding protein that inhibits PKR activation. These results indicate that m142 and m143 are both required for inhibition of the PKR-mediated host antiviral response.

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Nicholson, Iain P., Jane S. Sutherland, Tanya N. Chaudry, Earl L. Blewett, Peter A. Barry, Mary Nicholl i Chris M. Preston. "Properties of virion transactivator proteins encoded by primate cytomegaloviruses". Virology Journal 6, nr 1 (2009): 65. http://dx.doi.org/10.1186/1743-422x-6-65.

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Moulden, Jerome, Cathy Yea Won Sung, Ilija Brizic, Stipan Jonjic i William Britt. "Murine Models of Central Nervous System Disease following Congenital Human Cytomegalovirus Infections". Pathogens 10, nr 8 (21.08.2021): 1062. http://dx.doi.org/10.3390/pathogens10081062.

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Human cytomegalovirus infection of the developing fetus is a leading cause of neurodevelopmental disorders in infants and children, leading to long-term neurological sequela in a significant number of infected children. Current understanding of the neuropathogenesis of this intrauterine infection is limited because of the complexity of this infection, which includes maternal immunological responses that are overlaid on virus replication in the CNS during neurodevelopment. Furthermore, available data from human cases are observational, and tissues from autopsy studies have been derived from only the most severe infections. Animal models of this human infection are also limited by the strict species specificity of cytomegaloviruses. However, informative models including non-human primates and small animal models have been developed. These include several different murine models of congenital HCMV infection for the study of CMV neuropathogenesis. Although individual murine models do not completely recapitulate all aspects of the human infection, each model has provided significant information that has extended current understanding of the neuropathogenesis of this human infection. This review will compare and contrast different murine models in the context of available information from human studies of CNS disease following congenital HCMV infections.

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Rupp, Brigitte, Zsolt Ruzsics, Torsten Sacher i Ulrich H. Koszinowski. "Conditional Cytomegalovirus Replication In Vitro and In Vivo". Journal of Virology 79, nr 1 (1.01.2005): 486–94. http://dx.doi.org/10.1128/jvi.79.1.486-494.2005.

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ABSTRACT We have established a conditional gene expression system for cytomegalovirus which allows regulation of genes independently from the viral replication program. Due to the combination of all elements required for regulated expression in the same viral genome, conditional viruses can be studied in different cell lines in vitro and in the natural host in vivo. The combination of a self-sufficient tetracycline-regulated expression cassette and Flp recombinase-mediated insertion into the viral genome allowed fast construction of recombinant murine cytomegaloviruses carrying different conditional genes. The regulation of two reporter genes, the essential viral M50 gene and a dominant-negative mutant gene (m48.2) encoding the small capsid protein, was analyzed in more detail. In vitro, viral growth was regulated by the conditional expression of M50 by 3 orders of magnitude and up to a millionfold when the dominant-negative small capsid protein mutant was used. In vivo, viral growth of the dominant-negative mutant was reduced to detection limits in response to the presence of doxycycline in the organs of mice. We believe that this conditional expression system is applicable to genetic studies of large DNA viruses in general.

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Wild, Markus, Jintawee Kicuntod, Lisa Seyler, Christina Wangen, Luca D. Bertzbach, Andelé M. Conradie, Benedikt B. Kaufer i in. "Combinatorial Drug Treatments Reveal Promising Anticytomegaloviral Profiles for Clinically Relevant Pharmaceutical Kinase Inhibitors (PKIs)". International Journal of Molecular Sciences 22, nr 2 (8.01.2021): 575. http://dx.doi.org/10.3390/ijms22020575.

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Human cytomegalovirus (HCMV) is a human pathogenic herpesvirus associated with a variety of clinical symptoms. Current antiviral therapy is not always effective, so that improved drug classes and drug-targeting strategies are needed. Particularly host-directed antivirals, including pharmaceutical kinase inhibitors (PKIs), may help to overcome problems of drug resistance. Here, we focused on utilizing a selection of clinically relevant PKIs and determined their anticytomegaloviral efficacies. Particularly, PKIs directed to host or viral cyclin-dependent kinases, i.e., abemaciclib, LDC4297 and maribavir, exerted promising profiles against human and murine cytomegaloviruses. The anti-HCMV in vitro activity of the approved anti-cancer drug abemaciclib was confirmed in vivo using our luciferase-based murine cytomegalovirus (MCMV) animal model in immunocompetent mice. To assess drug combinations, we applied the Bliss independence checkerboard and Loewe additivity fixed-dose assays in parallel. Results revealed that (i) both affirmative approaches provided valuable information on anti-CMV drug efficacies and interactions, (ii) the analyzed combinations comprised additive, synergistic or antagonistic drug interactions consistent with the drugs’ antiviral mode-of-action, (iii) the selected PKIs, especially LDC4297, showed promising inhibitory profiles, not only against HCMV but also other α-, β- and γ-herpesviruses, and specifically, (iv) the combination treatment with LDC4297 and maribavir revealed a strong synergism against HCMV, which might open doors towards novel clinical options in the near future. Taken together, this study highlights the potential of therapeutic drug combinations of current developmental/preclinical PKIs.

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Wild, Markus, Jintawee Kicuntod, Lisa Seyler, Christina Wangen, Luca D. Bertzbach, Andelé M. Conradie, Benedikt B. Kaufer i in. "Combinatorial Drug Treatments Reveal Promising Anticytomegaloviral Profiles for Clinically Relevant Pharmaceutical Kinase Inhibitors (PKIs)". International Journal of Molecular Sciences 22, nr 2 (8.01.2021): 575. http://dx.doi.org/10.3390/ijms22020575.

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Human cytomegalovirus (HCMV) is a human pathogenic herpesvirus associated with a variety of clinical symptoms. Current antiviral therapy is not always effective, so that improved drug classes and drug-targeting strategies are needed. Particularly host-directed antivirals, including pharmaceutical kinase inhibitors (PKIs), may help to overcome problems of drug resistance. Here, we focused on utilizing a selection of clinically relevant PKIs and determined their anticytomegaloviral efficacies. Particularly, PKIs directed to host or viral cyclin-dependent kinases, i.e., abemaciclib, LDC4297 and maribavir, exerted promising profiles against human and murine cytomegaloviruses. The anti-HCMV in vitro activity of the approved anti-cancer drug abemaciclib was confirmed in vivo using our luciferase-based murine cytomegalovirus (MCMV) animal model in immunocompetent mice. To assess drug combinations, we applied the Bliss independence checkerboard and Loewe additivity fixed-dose assays in parallel. Results revealed that (i) both affirmative approaches provided valuable information on anti-CMV drug efficacies and interactions, (ii) the analyzed combinations comprised additive, synergistic or antagonistic drug interactions consistent with the drugs’ antiviral mode-of-action, (iii) the selected PKIs, especially LDC4297, showed promising inhibitory profiles, not only against HCMV but also other α-, β- and γ-herpesviruses, and specifically, (iv) the combination treatment with LDC4297 and maribavir revealed a strong synergism against HCMV, which might open doors towards novel clinical options in the near future. Taken together, this study highlights the potential of therapeutic drug combinations of current developmental/preclinical PKIs.

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Schupp, Anna-Kathrin, Mirko Trilling, Stephanie Rattay, Vu Thuy Khanh Le-Trilling, Katrin Haselow, Jan Stindt, Albert Zimmermann, Dieter Häussinger, Hartmut Hengel i Dirk Graf. "Bile Acids Act as Soluble Host Restriction Factors Limiting Cytomegalovirus Replication in Hepatocytes". Journal of Virology 90, nr 15 (11.05.2016): 6686–98. http://dx.doi.org/10.1128/jvi.00299-16.

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ABSTRACTThe liver constitutes a prime site of cytomegalovirus (CMV) replication and latency. Hepatocytes produce, secrete, and recycle a chemically diverse set of bile acids, with the result that interactions between bile acids and cytomegalovirus inevitably occur. Here we determined the impact of naturally occurring bile acids on mouse CMV (MCMV) replication. In primary mouse hepatocytes, physiological concentrations of taurochenodeoxycholic acid (TCDC), glycochenodeoxycholic acid, and to a lesser extent taurocholic acid significantly reduced MCMV-induced gene expression and diminished the generation of virus progeny, while several other bile acids did not exert antiviral effects. The anticytomegalovirus activity required active import of bile acids via the sodium-taurocholate-cotransporting polypeptide (NTCP) and was consistently observed in hepatocytes but not in fibroblasts. Under conditions in which alpha interferon (IFN-α) lacks antiviral activity, physiological TCDC concentrations were similarly effective as IFN-γ. A detailed investigation of distinct steps of the viral life cycle revealed that TCDC deregulates viral transcription and diminishes global translation in infected cells.IMPORTANCECytomegaloviruses are members of theBetaherpesvirinaesubfamily. Primary infection leads to latency, from which cytomegaloviruses can reactivate under immunocompromised conditions and cause severe disease manifestations, including hepatitis. The present study describes an unanticipated antiviral activity of conjugated bile acids on MCMV replication in hepatocytes. Bile acids negatively influence viral transcription and exhibit a global effect on translation. Our data identify bile acids as site-specific soluble host restriction factors against MCMV, which may allow rational design of anticytomegalovirus drugs using bile acids as lead compounds.

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Mandal, Pratyusha, Lynsey N. Nagrani, Liliana Hernandez, Anita Louise McCormick, Christopher P. Dillon, Heather S. Koehler, Linda Roback, Emad S. Alnemri, Douglas R. Green i Edward S. Mocarski. "Multiple Autonomous Cell Death Suppression Strategies Ensure Cytomegalovirus Fitness". Viruses 13, nr 9 (27.08.2021): 1707. http://dx.doi.org/10.3390/v13091707.

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Programmed cell death pathways eliminate infected cells and regulate infection-associated inflammation during pathogen invasion. Cytomegaloviruses encode several distinct suppressors that block intrinsic apoptosis, extrinsic apoptosis, and necroptosis, pathways that impact pathogenesis of this ubiquitous herpesvirus. Here, we expanded the understanding of three cell autonomous suppression mechanisms on which murine cytomegalovirus relies: (i) M38.5-encoded viral mitochondrial inhibitor of apoptosis (vMIA), a BAX suppressor that functions in concert with M41.1-encoded viral inhibitor of BAK oligomerization (vIBO), (ii) M36-encoded viral inhibitor of caspase-8 activation (vICA), and (iii) M45-encoded viral inhibitor of RIP/RHIM activation (vIRA). Following infection of bone marrow-derived macrophages, the virus initially deflected receptor-interacting protein kinase (RIPK)3-dependent necroptosis, the most potent of the three cell death pathways. This process remained independent of caspase-8, although suppression of this apoptotic protease enhances necroptosis in most cell types. Second, the virus deflected TNF-mediated extrinsic apoptosis, a pathway dependent on autocrine TNF production by macrophages that proceeds independently of mitochondrial death machinery or RIPK3. Third, cytomegalovirus deflected BCL-2 family protein-dependent mitochondrial cell death through combined TNF-dependent and -independent signaling even in the absence of RIPK1, RIPK3, and caspase-8. Furthermore, each of these cell death pathways dictated a distinct pattern of cytokine and chemokine activation. Therefore, cytomegalovirus employs sequential, non-redundant suppression strategies to specifically modulate the timing and execution of necroptosis, extrinsic apoptosis, and intrinsic apoptosis within infected cells to orchestrate virus control and infection-dependent inflammation. Virus-encoded death suppressors together hold control over an intricate network that upends host defense and supports pathogenesis in the intact mammalian host.

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