Articles de revues : « HAdV E1A »

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Singh, Gurdeep, Ashrafali M. Ismail, Jeong Yoon Lee, Mirja Ramke, Ji Sun Lee, David W. Dyer, Donald Seto, Jaya Rajaiya et and James Chodosh. « Divergent Evolution of E1A CR3 in Human Adenovirus Species D ». Viruses 11, n^o 2 (8 février 2019) : 143. http://dx.doi.org/10.3390/v11020143.

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Adenovirus E1A is the first viral protein expressed during infection. E1A controls critical aspects of downstream viral gene expression and cell cycle deregulation, and its function is thought to be highly conserved among adenoviruses. Various bioinformatics analyses of E1A from 38 human adenoviruses of species D (HAdV-D), including likelihood clade model partitioning, provided highly significant evidence of divergence of HAdV-Ds into two distinct groups for the conserved region 3 (CR3), present only in the E1A 13S isoform. This variance within E1A 13S of HAdV-Ds was not found in any other human adenovirus (HAdV) species. By protein sequence and structural analysis, the zinc finger motif of E1A CR3, previously shown as critical for transcriptional activation, showed the greatest differences. Subsequent codon usage bias analysis revealed substantial divergence in E1A 13S between the two groups of HAdV-Ds, suggesting that these two sub-groups of HAdV-D evolved under different cellular conditions. Hence, HAdV-D E1A embodies a previously unappreciated evolutionary divergence among HAdVs.

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Zhang, Ali, Tanner Tessier, Kristianne Galpin, Cason King, Steven Gameiro, Wyatt Anderson, Ahmed Yousef, Wen Qin, Shawn Li et Joe Mymryk. « The Transcriptional Repressor BS69 is a Conserved Target of the E1A Proteins from Several Human Adenovirus Species ». Viruses 10, n^o 12 (22 novembre 2018) : 662. http://dx.doi.org/10.3390/v10120662.

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Early region 1A (E1A) is the first viral protein produced upon human adenovirus (HAdV) infection. This multifunctional protein transcriptionally activates other HAdV early genes and reprograms gene expression in host cells to support productive infection. E1A functions by interacting with key cellular regulatory proteins through short linear motifs (SLiMs). In this study, the molecular determinants of interaction between E1A and BS69, a cellular repressor that negatively regulates E1A transactivation, were systematically defined by mutagenesis experiments. We found that a minimal sequence comprised of MPNLVPEV, which contains a conserved PXLXP motif and spans residues 112–119 in HAdV-C5 E1A, was necessary and sufficient in binding to the myeloid, Nervy, and DEAF-1 (MYND) domain of BS69. Our study also identified residues P113 and L115 as critical for this interaction. Furthermore, the HAdV-C5 and -A12 E1A proteins from species C and A bound BS69, but those of HAdV-B3, -E4, -D9, -F40, and -G52 from species B, E, D, F, and G, respectively, did not. In addition, BS69 functioned as a repressor of E1A-mediated transactivation, but only for HAdV-C5 and HAdV-A12 E1A. Thus, the PXLXP motif present in a subset of HAdV E1A proteins confers interaction with BS69, which serves as a negative regulator of E1A mediated transcriptional activation.

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Ip, Wing-Hang, Britta Wilkens, Anastasia Solomatina, Judith Martin, Michael Melling, Paloma Hidalgo, Luca D. Bertzbach, Thomas Speiseder et Thomas Dobner. « Differential Regulation of Cellular FAM111B by Human Adenovirus C Type 5 E1 Oncogenes ». Viruses 13, n^o 6 (28 mai 2021) : 1015. http://dx.doi.org/10.3390/v13061015.

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The adenovirus type 5 (HAdV-C5) E1 transcription unit encodes regulatory proteins that are essential for viral replication and transformation. Among these, E1A and E1B-55K act as key multifunctional HAdV-C5 proteins involved in various steps of the viral replication cycle and in virus-induced cell transformation. In this context, HAdV-C5-mediated dysregulations of cellular factors such as the tumor suppressors p53 and pRB have been intensively investigated. However, cellular components of downstream events that could affect infection and viral transformation are widely unknown. We recently observed that cellular FAM111B is highly regulated in an E1A-dependent fashion. Intriguingly, previous reports suggest that FAM111B might play roles in tumorigenesis, but its exact functions are not known to date. Here, we set out to investigate the role of FAM111B in HAdV-C5 infections. We found that (i) FAM111B levels are upregulated early and downregulated late during infection, that (ii) FAM111B expression is differentially regulated, that (iii) FAM111B expression levels depend on the presence of E1B-55K and E4orf6 and that (iv) a FAM111B knockdown increases HAdV-C5 replication. Our data indicate that FAM111B acts as an anti-adenoviral host factor that is involved in host cell defense mechanisms in productive HAdV-C5 infection. Moreover, these findings suggest that FAM111B might play an important role in the host antiviral immune response that is counteracted by HAdV-C5 E1B-55K and E4orf6 oncoproteins.

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Prusinkiewicz, Martin A., Jessie Tu, Mackenzie J. Dodge, Katelyn M. MacNeil, Sandi Radko-Juettner, Gregory J. Fonseca, Peter Pelka et Joe S. Mymryk. « Differential Effects of Human Adenovirus E1A Protein Isoforms on Aerobic Glycolysis in A549 Human Lung Epithelial Cells ». Viruses 12, n^o 6 (3 juin 2020) : 610. http://dx.doi.org/10.3390/v12060610.

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Viruses alter a multitude of host-cell processes to create a more optimal environment for viral replication. This includes altering metabolism to provide adequate substrates and energy required for replication. Typically, viral infections induce a metabolic phenotype resembling the Warburg effect, with an upregulation of glycolysis and a concurrent decrease in cellular respiration. Human adenovirus (HAdV) has been observed to induce the Warburg effect, which can be partially attributed to the adenovirus protein early region 4, open reading frame 1 (E4orf1). E4orf1 regulates a multitude of host-cell processes to benefit viral replication and can influence cellular metabolism through the transcription factor avian myelocytomatosis viral oncogene homolog (MYC). However, E4orf1 does not explain the full extent of Warburg-like HAdV metabolic reprogramming, especially the accompanying decrease in cellular respiration. The HAdV protein early region 1A (E1A) also modulates the function of the infected cell to promote viral replication. E1A can interact with a wide variety of host-cell proteins, some of which have been shown to interact with metabolic enzymes independently of an interaction with E1A. To determine if the HAdV E1A proteins are responsible for reprogramming cell metabolism, we measured the extracellular acidification rate and oxygen consumption rate of A549 human lung epithelial cells with constitutive endogenous expression of either of the two major E1A isoforms. This was followed by the characterization of transcript levels for genes involved in glycolysis and cellular respiration, and related metabolic pathways. Cells expressing the 13S encoded E1A isoform had drastically increased baseline glycolysis and lower maximal cellular respiration than cells expressing the 12S encoded E1A isoform. Cells expressing the 13S encoded E1A isoform exhibited upregulated expression of glycolysis genes and downregulated expression of cellular respiration genes. However, tricarboxylic acid cycle genes were upregulated, resembling anaplerotic metabolism employed by certain cancers. Upregulation of glycolysis and tricarboxylic acid cycle genes was also apparent in IMR-90 human primary lung fibroblast cells infected with a HAdV-5 mutant virus that expressed the 13S, but not the 12S encoded E1A isoform. In conclusion, it appears that the two major isoforms of E1A differentially influence cellular glycolysis and oxidative phosphorylation and this is at least partially due to the altered regulation of mRNA expression for the genes in these pathways.

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Roy, Soumitra, David S. Clawson, Virginie S. Adam, Angelica Medina et James M. Wilson. « Construction of gene transfer vectors based on simian adenovirus 7 ». Journal of General Virology 92, n^o 8 (1 août 2011) : 1749–53. http://dx.doi.org/10.1099/vir.0.032300-0.

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The complete nucleotide sequence of an isolate of simian adenovirus 7 (SAdV-7) was determined. The genome organization of this isolate was found to be similar to that of other primate adenoviruses with two principal notable points: severe truncation of the E1A and E1B 19K proteins and an E3 region encoding only the 12.5K homologue. The viral gene products of SAdV-7 are most closely related to simian adenovirus 1 (SAdV-1), and like SAdV-1, are related to the human adenovirus species HAdV-F, such as the enteric adenoviruses HAdV-40 and HAdV-41 and the recently defined HAdV-G (HAdV-52). Two kinds of gene transfer vectors were made: a replication-competent SAdV-7-based vector with no genomic deletion, and a standard replication-incompetent vector deleted for E1. Importantly, the E1-deleted vector could be propagated to high titre by trans-complementation in human HEK 293 cells.

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Kim, Misoon, Mi Young Lim et GwangPyo Ko. « Enhancement of Enteric Adenovirus Cultivation by Viral Transactivator Proteins ». Applied and Environmental Microbiology 76, n^o 8 (5 février 2010) : 2509–16. http://dx.doi.org/10.1128/aem.02224-09.

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ABSTRACT Human enteric adenoviruses (HAdVs; serotypes 40 and 41) are important waterborne and food-borne pathogens. However, HAdVs are fastidious, are difficult to cultivate, and do not produce a clear cytopathic effect during cell culture within a reasonable time. Thus, we examined whether the viral transactivator proteins cytomegalovirus (CMV) IE1 and hepatitis B virus (HBV) X promoted the multiplication of HAdVs. Additionally, we constructed a new 293 cell line expressing CMV IE1 protein for cultivation assays. We analyzed the nucleic acid sequences of the promoter regions of both E1A and hexon genes, which are considered to be the most important regions for HAdV replication. Expression of either HBV X or CMV IE1 protein significantly increased the promoter activities of E1A and hexon genes of HAdVs by as much as 14-fold during cell cultivation. The promotion of HAdV expression was confirmed by increased levels of both adenoviral DNA and mRNA expression. Finally, the newly developed 293 cell line expressing CMV IE1 protein showed an increase in viral DNA ranging from 574% to 619% compared with the conventional 293 cell line. These results suggest that the newly constructed cell line could be useful for efficient cultivation and research of fastidious HAdVs.

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Dalidowska, Iga, Olga Gazi, Dorota Sulejczak, Maciej Przybylski et Pawel Bieganowski. « Heat Shock Protein 90 Chaperones E1A Early Protein of Adenovirus 5 and Is Essential for Replication of the Virus ». International Journal of Molecular Sciences 22, n^o 4 (18 février 2021) : 2020. http://dx.doi.org/10.3390/ijms22042020.

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Adenovirus infections tend to be mild, but they may pose a serious threat for young and immunocompromised individuals. The treatment is complicated because there are no approved safe and specific drugs for adenovirus infections. Here, we present evidence that 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG), an inhibitor of Hsp90 chaperone, decreases the rate of human adenovirus 5 (HAdV-5) replication in cell cultures by 95%. 17-AAG inhibited the transcription of early and late genes of HAdV-5, replication of viral DNA, and expression of viral proteins. 6 h after infection, Hsp90 inhibition results in a 6.3-fold reduction of the newly synthesized E1A protein level without a decrease in the E1A mRNA level. However, the Hsp90 inhibition does not increase the decay rate of the E1A protein that was constitutively expressed in the cell before exposure to the inhibitor. The co-immunoprecipitation proved that E1A protein interacted with Hsp90. Altogether, the presented results show, for the first time. that Hsp90 chaperones newly synthesized, but not mature, E1A protein. Because E1A serves as a transcriptional co-activator of adenovirus early genes, the anti-adenoviral activity of the Hsp90 inhibitor might be explained by the decreased E1A level.

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Kosulin, Karin. « Intestinal HAdV Infection : Tissue Specificity, Persistence, and Implications for Antiviral Therapy ». Viruses 11, n^o 9 (30 août 2019) : 804. http://dx.doi.org/10.3390/v11090804.

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Human adenovirus (HAdV) causes infections predominantly in early childhood and the tissue tropism of specific HAdV species determines the clinical manifestation, including infections of the gastrointestinal tract, respiratory tract, and keratoconjunctivitis. Why HAdV shows such a tropism has not yet been fully elucidated, but in the intestine different mechanisms for virus entry or resistence to immune modulatory factors have been described. Recently identified antiviral strategies by interferons provide evidence about the repression of E1A and maybe even promote HAdV persistence. The presence of HAdV in a persistent status in the gut is of importance in the setting of pediatric stem cell transplant recipients where HAdV detection in stool usually preceds clinical signs and severe infections are related to mortality. The reactivation of persistent intestinal HAdV infections in these patients needs further investigation also with regard to successful therapy options. In addition, several newly identified recombinant HAdV types have been isolated from stool samples, thus raising the question of possible recombination events in the gut. In this review, intestinal HAdV infections are discussed in relation to the tissue tropism, persistence, recombination, and new in-vitro models to enhance the knowledge about virus–host interactions and support the development of new treatment approaches.

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Prusinkiewicz, Martin A., et Joe S. Mymryk. « Metabolic Reprogramming of the Host Cell by Human Adenovirus Infection ». Viruses 11, n^o 2 (8 février 2019) : 141. http://dx.doi.org/10.3390/v11020141.

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Viruses are obligate intracellular parasites that alter many cellular processes to create an environment optimal for viral replication. Reprogramming of cellular metabolism is an important, yet underappreciated feature of many viral infections, as this ensures that the energy and substrates required for viral replication are available in abundance. Human adenovirus (HAdV), which is the focus of this review, is a small DNA tumor virus that reprograms cellular metabolism in a variety of ways. It is well known that HAdV infection increases glucose uptake and fermentation to lactate in a manner resembling the Warburg effect observed in many cancer cells. However, HAdV infection induces many other metabolic changes. In this review, we integrate the findings from a variety of proteomic and transcriptomic studies to understand the subtleties of metabolite and metabolic pathway control during HAdV infection. We review how the E4ORF1 protein of HAdV enacts some of these changes and summarize evidence for reprogramming of cellular metabolism by the viral E1A protein. Therapies targeting altered metabolism are emerging as cancer treatments, and similar targeting of aberrant components of virally reprogrammed metabolism could have clinical antiviral applications.

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Osipov, Ivan D., Valeriia A. Vasikhovskaia, Daria S. Zabelina, Sergei S. Kutseikin, Antonina A. Grazhdantseva, Galina V. Kochneva, Julia Davydova, Sergey V. Netesov et Margarita V. Romanenko. « Development of Oncolytic Vectors Based on Human Adenovirus Type 6 for Cancer Treatment ». Viruses 15, n^o 1 (7 janvier 2023) : 182. http://dx.doi.org/10.3390/v15010182.

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Human Adenovirus type 6 (HAdV-C6) is a promising candidate for the development of oncolytic vectors as it has low seroprevalence and the intrinsic ability to evade tissue macrophages. However, its further development as a therapeutic agent is hampered by the lack of convenient cloning methods. We have developed a novel technology when a shuttle plasmid carrying the distal genome parts with modified E1A and E3 regions is recombined in vitro with the truncated HAdV-C6 genome. Using this approach, we have constructed a novel Ad6-hT-GM vector controlled by the hTERT promoter and expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) instead of 6.7K and gp19K E3 proteins. We have demonstrated that control by the hTERT promoter may result in delayed viral replication, which nevertheless does not significantly change the cytotoxic ability of recombinant viruses. The insertion of the transgene by displacing the E3-6.7K/gp19K region does not drastically change the expression patterns of E3 genes; however, mild changes in expression from major late promoter were observed. Finally, we have demonstrated that the treatment of human breast cancer xenografts in murine models with Ad6-hT-GM significantly decreased the tumor volume and improved survival time compared to mock-treated mice.

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Bürck, Carolin, Andreas Mund, Julia Berscheminski, Lisa Kieweg, Sarah Müncheberg, Thomas Dobner et Sabrina Schreiner. « KAP1 Is a Host Restriction Factor That Promotes Human Adenovirus E1B-55K SUMO Modification ». Journal of Virology 90, n^o 2 (4 novembre 2015) : 930–46. http://dx.doi.org/10.1128/jvi.01836-15.

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ABSTRACTOnce transported to the replication sites, human adenoviruses (HAdVs) need to ensure decondensation and transcriptional activation of their viral genomes to synthesize viral proteins and initiate steps to reprogram the host cell for viral replication. These early stages during adenoviral infection are poorly characterized but represent a decisive moment in the establishment of a productive infection. Here, we identify a novel host viral restriction factor, KAP1. This heterochromatin-associated transcription factor regulates the dynamic organization of the host chromatin structure via its ability to influence epigenetic marks and chromatin compaction. In response to DNA damage, KAP1 is phosphorylated and functionally inactive, resulting in chromatin relaxation. We discovered that KAP1 posttranslational modification is dramatically altered during HAdV infection to limit the antiviral capacity of this host restriction factor, which represents an essential step required for efficient viral replication. Conversely, we also observed during infection an HAdV-mediated decrease of KAP1 SUMO moieties, known to promote chromatin decondensation events. Based on our findings, we provide evidence that HAdV induces KAP1 deSUMOylation to minimize epigenetic gene silencing and to promote SUMO modification of E1B-55K by a so far unknown mechanism.IMPORTANCEHere we describe a novel cellular restriction factor for human adenovirus (HAdV) that sheds light on very early modulation processes in viral infection. We reported that chromatin formation and cellular SWI/SNF chromatin remodeling play key roles in HAdV transcriptional regulation. We observed that the cellular chromatin-associated factor and epigenetic reader SPOC1 represses HAdV infection and gene expression. Here, we illustrate the role of the SPOC1-interacting factor KAP1 during productive HAdV growth. KAP1 binds to the viral E1B-55K protein, promoting its SUMO modification, therefore illustrating a crucial step for efficient viral replication. Simultaneously, KAP1 posttranslational modification is dramatically altered during infection. We observed an HAdV-mediated decrease in KAP1 SUMOylation, known to promote chromatin decondensation events. These findings indicate that HAdV induces the loss of KAP1 SUMOylation to minimize epigenetic gene silencing and to promote the SUMO modification of E1B-55K by a so far unknown mechanism.

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Avvakumov, Nikita, Russ Wheeler, Jean Claude D'Halluin et Joe S. Mymryk. « Comparative Sequence Analysis of the Largest E1A Proteins of Human and Simian Adenoviruses ». Journal of Virology 76, n^o 16 (15 août 2002) : 7968–75. http://dx.doi.org/10.1128/jvi.76.16.7968-7975.2002.

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ABSTRACT The early region 1A (E1A) gene is the first gene expressed after infection with adenovirus and has been most extensively characterized in human adenovirus type 5 (hAd5). The E1A proteins interact with numerous cellular regulatory proteins, influencing a variety of transcriptional and cell cycle events. For this reason, these multifunctional proteins have been useful as tools for dissecting pathways regulating cell growth and gene expression. Despite the large number of studies using hAd5 E1A, relatively little is known about the function of the E1A proteins of other adenoviruses. In 1985, a comparison of E1A sequences from three human and one simian adenovirus identified three regions with higher overall levels of sequence conservation designated conserved regions (CR) 1, 2, and 3. As expected, these regions are critical for a variety of E1A functions. Since that time, the sequences of several other human and simian adenovirus E1A proteins have been determined. Using these, and two additional sequences that we determined, we report here a detailed comparison of the sequences of 15 E1A proteins representing each of the six hAd subgroups and several simian adenoviruses. These analyses refine the positioning of CR1, 2, and 3; define a fourth CR located near the carboxyl terminus of E1A; and suggest several new functions for E1A.

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Fiedler, Marie, Wing-Hang Ip, Helga Hofmann-Sieber, Britta Wilkens, Francis K. Nkrumah, Wenli Zhang, Anja Ehrhardt, Luca D. Bertzbach et Thomas Dobner. « Protein–Protein Interactions Facilitate E4orf6-Dependent Regulation of E1B-55K SUMOylation in HAdV-C5 Infection ». Viruses 14, n^o 3 (24 février 2022) : 463. http://dx.doi.org/10.3390/v14030463.

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The human adenovirus type C5 (HAdV-C5) E1B-55K protein is a multifunctional regulator of HAdV-C5 replication, participating in many processes required for maximal virus production. Its multifunctional properties are primarily regulated by post-translational modifications (PTMs). The most influential E1B-55K PTMs are phosphorylation at highly conserved serine and threonine residues at the C-terminus, and SUMO conjugation to lysines 104 (K104) and 101 (K101) situated in the N-terminal region of the protein, which have been shown to regulate each other. Reversible SUMO conjugation provides a molecular switch that controls key functions of the viral protein, including intracellular trafficking and viral immune evasion. Interestingly, SUMOylation at SUMO conjugation site (SCS) K104 is negatively regulated by another multifunctional HAdV-C5 protein, E4orf6, which is known to form a complex with E1B-55K. To further evaluate the role of E4orf6 in the regulation of SUMO conjugation to E1B-55K, we analyzed different virus mutants expressing E1B-55K proteins with amino acid exchanges in both SCS (K101 and K104) in the presence or absence of E4orf6. We could exclude phosphorylation as factor for E4orf6-mediated reduction of E1B-55K SUMOylation. In fact, we demonstrate that a direct interaction between E1B-55K and E4orf6 is required to reduce E1B-55K SUMOylation. Additionally, we show that an E4orf6-mediated decrease of SUMO conjugation to K101 and K104 result in impaired co-localization of E1B-55K and SUMO in viral replication compartments. These findings indicate that E4orf6 inhibits E1B-55K SUMOylation, which could favor assembly of E4orf6-dependent E3 ubiquitin ligase complexes that are known to degrade a variety of host restriction factors by proteasomal degradation and, thereby, promote viral replication.

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Vijayalingam, S., T. Subramanian, Ling-jun Zhao et G. Chinnadurai. « The Cellular Protein Complex Associated with a Transforming Region of E1A Contains c-MYC ». Journal of Virology 90, n^o 2 (11 novembre 2015) : 1070–79. http://dx.doi.org/10.1128/jvi.02039-15.

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ABSTRACTThe cell-transforming activity of human adenovirus 5 (hAd5) E1A is mediated by the N-terminal half of E1A, which interacts with three different major cellular protein complexes, p300/CBP, TRRAP/p400, and pRb family members. Among these protein interactions, the interaction of pRb family proteins with conserved region 2 (CR2) of E1A is known to promote cell proliferation by deregulating the activities of E2F family transcription factors. The functional consequences of interaction with the other two protein complexes in regulating the transforming activity of E1A are not well defined. Here, we report that the E1A N-terminal region also interacted with the cellular proto-oncoprotein c-MYC and the homolog of enhancer of yellow 2 (ENY2). Our results suggested that these proteins interacted with an essential E1A transforming domain spanning amino acid residues 26 to 35 which also interacted with TRRAP and p400. Small interfering RNA (siRNA)-mediated depletion of TRRAP reduced c-MYC interaction with E1A, while p400 depletion did not. In contrast, depletion of TRRAP enhanced ENY2 interaction with E1A, suggesting that ENY2 and TRRAP may interact with E1A in a competitive manner. The same E1A region additionally interacted with the constituents of a deubiquitinase complex consisting of USP22, ATXN7, and ATXN7L3 via TRRAP. Acute short hairpin RNA (shRNA)-mediated depletion of c-MYC reduced the E1A transforming activity, while depletion of ENY2 and MAX did not. These results suggested that the association of c-MYC with E1A may, at least partially, play a role in the E1A transformation activity, independently of MAX.IMPORTANCEThe transforming region of adenovirus E1A consists of three short modules which complex with different cellular protein complexes. The mechanism by which one of the transforming modules, CR2, promotes cell proliferation, through inactivating the activities of the pRb family proteins, is better understood than the activities of the other domains. Our analysis of the E1A proteome revealed the presence of the proto-oncoprotein c-MYC and of ENY2. We mapped these interactions to a critical transforming module of E1A that was previously known to interact with the scaffolding molecule TRRAP and the E1A-binding protein p400. We showed that c-MYC interacted with E1A through TRRAP, while ENY2 interacted with it independently. The data reported here indicated that depletion of c-MYC in normal human cells reduced the transforming activity of E1A. Our result raises a novel paradigm in oncogenic transformation by a DNA viral oncogene, the E1A gene, that may exploit the activity of a cellular oncogene, the c-MYC gene, in addition to inactivation of the tumor suppressors, such as pRb.

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Cromeans, Theresa L., Amy M. Kahler et Vincent R. Hill. « Inactivation of Adenoviruses, Enteroviruses, and Murine Norovirus in Water by Free Chlorine and Monochloramine ». Applied and Environmental Microbiology 76, n^o 4 (18 décembre 2009) : 1028–33. http://dx.doi.org/10.1128/aem.01342-09.

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ABSTRACT Inactivation of infectious viruses during drinking water treatment is usually achieved with free chlorine. Many drinking water utilities in the United States now use monochloramine as a secondary disinfectant to minimize disinfectant by-product formation and biofilm growth. The inactivation of human adenoviruses 2, 40, and 41 (HAdV2, HAdV40, and HAdV41), coxsackieviruses B3 and B5 (CVB3 and CVB5), echoviruses 1 and 11 (E1 and E11), and murine norovirus (MNV) are compared in this study. Experiments were performed with 0.2 mg of free chlorine or 1 mg of monochloramine/liter at pH 7 and 8 in buffered reagent-grade water at 5°C. CT values (disinfectant concentration × time) for 2- to 4-log10 (99 to 99.99%) reductions in virus titers were calculated by using the efficiency factor Hom model. The enteroviruses required the longest times for chlorine inactivation and MNV the least time. CVB5 required the longest exposure time, with CT values of 7.4 and 10 mg·min/liter (pH 7 and 8) for 4-log10 inactivation. Monochloramine disinfection was most effective for E1 (CT values ranged from 8 to 18 mg·min/liter for 2- and 3-log10 reductions, respectively). E11 and HAdV2 were the least susceptible to monochloramine disinfection (CT values of 1,300 and 1,600 mg-min/liter for 3-log10 reductions, respectively). Monochloramine inactivation was most successful for the adenoviruses, CVB5, and E1 at pH 7. A greater variation in inactivation rates between viruses was observed during monochloramine disinfection than during chlorine disinfection. These data will be useful in drinking water risk assessment studies and disinfection system planning.

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Chaiyawat, Pakaratee, Kongkiat Kulkantrakorn et Paskorn Sritipsukho. « Effectiveness of home rehabilitation for ischemic stroke ». Neurology International 1, n^o 1 (25 août 2009) : 36. http://dx.doi.org/10.4081/ni.2009.e10.

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The objective of this study was to develop and examine the effectiveness of an individual home rehabilitation program for patients with ischemic stroke. This was a randomized controlled trial in 60 patients with recent middle cerebral artery infarction. After hospital discharge for acute stroke care, they were randomly assigned to receive either a home rehabilitation program for three months (intervention group) or usual care (control group). We collected outcome data over three months after their discharge from the hospital. The Barthel Index (BI), the Modified Rankin Scale (MRS), the health-related quality-of-life index (EQ-5D), the Hospital Anxiety and Depression score (HADs), and the Thai Mental State Examination (TMSE) were used to analyze the outcomes. In the intervention group, all outcomes were significantly better (p

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Sapozhnikova, E., M. Sapozhnikov, E. Guryanova et N. Alekseeva. « AB1196 INFLUENCE OF NEUROPATHIC PAIN ON THE FUNCTIONAL STATUS OF ELDERLY PATIENTS WITH RHEUMATOID ARTHRITIS ». Annals of the Rheumatic Diseases 81, Suppl 1 (23 mai 2022) : 1713.2–1713. http://dx.doi.org/10.1136/annrheumdis-2022-eular.629.

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ObjectivesThe aim of the study was to study the influence of neuropathic pain on functional status in elderly patients with rheumatoid arthritis (RA) with moderate disease activity.MethodsMethods. The study included 115 geriatric patients who were divided into two groups. Group G1 included 80 patients (mean age 76.9 ± 9.6 years) with neuropathic pain, group G2 - 35 persons of comparable age (77.1 ± 8.6 years) without signs of neuropathic pain. Neuropathic pain was identified using the DN4 questionnaire. The RA activity in patients of both groups did not differ statistically significantly. All patients underwent a comprehensive geriatric assessment (CGA) to determine the functional status and diagnose geriatric syndromes [1]. All patients received basic anti-inflammatory drugs. Patients G1 and G2 were compared in terms of the following parameters, such as pain intensity according to a visual analogue scale (VAS, 0-100 mm), Rivermead Mobility Index (0-15), functional disorders according to International Classification of Function (ICF) (0-4), signs of anxiety and depression (HADS).ResultsAccording to the CGA data, senile asthenia syndrome was detected in 32 (40.2%) patients with neuropathic pain and in 10 (28.6%) patients without neuropathic pain (p = 0.035). The average number of geriatric syndromes in G1 was 6.06 ± 1.03, in group B - 4.5 ± 1.0 (p <0.05). Patients with G1 showed higher indices of pain severity according to VAS than in patients of the control group: 68.2 ± 10.1 and 52.1 ± 4.1 mm, respectively (p <0.001). In G1, patients had a significant decrease in mobility, in the domain «Activity and participation» in the ICF categories d450 (walking), d 540 (dressing), the indicator of dysfunction was 2.9 ± 0.3 versus 2.2 ± 0.2 (p = 0.049), there were more symptoms of anxiety and depression 56.5% and 35.2% (HADS ≥7; p <0.001), respectively.ConclusionElderly patients with chronic neuropathic pain have higher signs of senile asthenia and decreased mobility and physical functioning in daily life. It is necessary to include the help of a psychologist and occupational therapist in planning the most effective comprehensive strategies for the treatment and prevention of exacerbations of neuropathic pain.References[1]Guryanova E.A., Rechapova E.A., Sidyakina E.S. Effectiveness of Comprehensive Geriatric Assessment in Improving the Quality of Life of Older People and Reducing the Workload of Their Caregivers // Acta medica Eurasica. – 2021. – № 4. – С. 79–90. – URL: http://acta-medica-eurasica.ru/single/2021/4/9. DOI: 10.47026/2413- 4864-2021-4-79-90.Disclosure of InterestsNone declared

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Matthews, Graham. « Rice insect pests and their management. By E.A. "Short" Heinrichs, Francis Nwilene, Michael Stout, Buyung Hadi and Thais Freitas ». Outlooks on Pest Management 28, n^o 4 (1 août 2017) : 190. http://dx.doi.org/10.1564/v28_aug_13.

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Silvianti, Fitrilia, Dwi Siswanta, Nurul Hidayat Aprilita et Agung Abadi Kiswandono. « ADSORPTION CHARACTERISTIC OF IRON ONTO POLY[EUGENOL-CO-(DIVINYL BENZENE)] FROM AQUEOUS SOLUTION ». Jurnal Natural 17, n^o 2 (23 septembre 2017) : 108. http://dx.doi.org/10.24815/jn.v17i2.8076.

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A study on the adsorption characteristic of Iron onto Poly[eugenol-co-(divinyl benzene)] (EDVB) from aqueous solution has been conducted. EDVB was produced and characterized by using FTIR spectroscopy. The adsorption was studied by a batch method by considering the factors affecting the adsorption such as initial metal ion concentration, adsorption selectivity, and mechanism of adsorption using a sequential desorption method. The adsorption of Iron onto EDVB followed a pseudo-2 order kinetics model with the rate constant of 0,144 L2 mmol-1 min-1. The adsorption isotherm was studied with Tempkin, Langmuir and Freundlich models. The adsorption capacity (Qmax) obtained by Langmuir isotherms was 250mg.L-1 while the equilibrium value was 0.8 Lmg-1. A competitive adsorption study showed that EDVB is adsorbed selectively towards Iron rather than Chromium, Coppers and Cadmium ions. The interaction type of Iron onto EDVB was determined by a sequential desorption.Keywords: Polyeugenol; divinyl benzene (DVB); adsorption; Iron; FeReferencesAbasi, C. Y.; Abia, A.A.; Igwe, J.C. Adsorption of Iron (III), Lead (II) and Cadmium (II) Ions by Unmodified Raphia Palm (Raphia hookeri) Fruit Endocarp. Environ. Res. 2011, 5 (3), 104-113, ISSN: 1994-5396, Medwell Journals. DOI: 10.3923/erj.2011.104.113Baes, F. C.; Mesmer, R. E. The Hydrolisis of Cations; John Wiley: New York, 1976Bakatula, E.N.; Cukrowska, E.M.; Weiersbye, L.; Mihali-Cozmuta, L.;Tutu, H. Removal of toxic elements from aqueous solution using bentonite modified with L-histidine. Water Sci. Technol.2014, 70 (12),2022-2030, DOI: 10.2166/wst.2014.450Bhattacharyya, K.G.; Gupta, S.S. Adsorption of Fe(III) from Water by Natural and Acid Activated Clays: Studies on equilibrium isotherm, kinetics and thermodynamics of interactions. Adsorption. 2006, 12 (3), 185-204,DOI : 10.1007/s10450-006-0145-0Carmona, M..; Lucas, A.D.; Valverde, J.L.; Velasco, B.; Rodriguez, J.F. Combined adsorption and ion exchange equilibrium of phenol on Amberlite IRA-420.Chem. Eng. J.2006, 117, 155-160, Doi : 10.1016/j.cej.2005.12.013Debnath, S.; Ghosh, U.C. Kinetics, isotherm and thermodynamics for Cr(III) and Cr(VI) adsorption from aqueous solutions by crystalline hydrous titanium oxide. J. Chem. Thermodin. 2008, 40: 67-77, DOI: 10.1016/j.jct.2007.05.014Djunaidi, M.C.; Jumina; Siswanta, D.; Ulbricht, M. Selective Transport of Fe(III) Using Polyeugenol as Functional Polymer with Ionic Imprinted Polymer Membrane Method. Asian J. Chem. 2015, 27 (12): 4553-4562, DOI : 10.14233/ajchem.2015.19228Febriasari, A.; Siswanta, D.; Kiswandono, A.A.; Aprilita, N.H. Evaluation of Phenol Transport Using Polymer Inclusion Membrane (PIM) with Polyeugenol as a Carrier. Jurnal Rekayasa Kimia dan Lingkungan. 2016, Vol. 11, No. 2, 99-106, DOI: 10.23955/rkl.v11i2.5112Foldesova, M.; Dillinger, P.; Luckac, P. Sorption and Desorption of Fe(III) on Natural and chemically modified zeolite. J. Radioanal. Nucl. Chem. 1999, Vol. 242, No. 1 (1999), 227-230, DOI: 10.1007/BF02345926Gupta, V.K.;Sharma, S. Removal of cadmium and zinc from aqueous solutions using mud.Environ. Sci. Technol. 2002, 36: 3612-3617, DOI: 10.1021/es020010vHandayani, D.S. Sintesis kopoli(eugenol-DVB) sulfonat dari Eugenol Komponen Utama Minyak Cengkeh Szygium aromaticum (Synthesis of copoly(eugenol-DVB) sulfonic from main components of eugenol clove oil Szygium aromaticum). Biopharmacy Journal of Pharmacological and Biological Sciences. 2004, 2 (2): 53-57 ISSN: 1693-2242. url : https://eprints.uns.ac.id/id/eprint/856Harimu, L.; Matsjeh, S.; Siswanta, D.; Santosa, S.J. Synthesis of Polyeugenyl Oxyacetic Acid as Carrier to Separate Heavy Metal Ion Fe(III), Cr(III), Cu(II), Ni(II), Co(II), and Pb(II) that Using Solvent Extraction Mehod. Indo. J. Chem. 2009, 9 (2): 261-266.Ho, Y.S.; McKay, G. Pseudo-second Order Model for Sorption Processes. Process. Biochem. 1999, 34, 451-465, DOI: 10.1016/S0032-9592(98)00112-5Ho, Y.S.; McKay, G.; Wase, D.A.J.;Forster, C.F. Study of Sorption Divalent Metal Ions on to Peat. Adsorpt. Sci. Technol. 2000, 18: 639-650. DOI : 10.1260/0263617001493693Indah, S.; Helard, D.;Sasmita, A. Utilization of maize husk (Zea mays L.) as low-cost adsorbent in removal of iron from aqueous solution. Water Sci. Technol. 2016, 73 (12), 2929-2935, DOI: 10.2166/wst.2016.154Kiswandono, A.A.; Siswanta, D.; Aprilita, N.H.; Santosa, S.J. Transport of Phenol through inclusion polymer membrane (PIM) using copoly(Eugenol-DVB) as membrane carries. Indo .J. Chem. 2012, 12 (2): 105-112. Doi : 10.22146/ijc.667Kousalya, N.; Gandhi, M.R.; Sundaram, C.S.; Meenakshi, S. Synthesis of nano-hydroxyapatite chitin/chitosan hybrid bio-composites for the removal of Fe(III).Carbohyd. Polym. 2010, 82: 594-599, DOI:10.1016/j.carbpol.2010.05.013Kumar, K.V.; Porkodi, K.;Rocha, F. Langmuir-Hinshelwood kinetics – A theoretical study, Catalysis Communications. 2008, 9: 82-84, DOI:10.1016/j.catcom.2007.05.019Masel, R.I. Principles Adsorption and Reaction on Solid Surface; John Wiley & Sons: Canada, 1996Moore, J. W.; Pearson, R.G. Kinetics and Mechanism Third Edition; John Wiley & Sons: Canada, 1981.Ngah, W.S.W.; Ghani, S.A.; Kamari, A. Adsorption Behaviour of Fe(II) and Fe(III) Ions in Aqueous Solution on Chitosan and Cross-linked Chitosan Beads. Bioresource. Technol. 2005, 96: 443-450. DOI:10.1016/j.biortech.2004.05.022Rahim, E.A.; Sanda, F.; Masuda, T. Synthesis and Properties of Novel Eugenol-Based Polymers. Polymer Bulletin. 2004, Vol. 5, 93-100, DOI: 10.1007/s00289-004-0272-2Samarghandi, M.R.; Hadi. M.; Moayedi, M.; Askari, F.B. 2009. Two Parameter Isotherms of Methyl Orange Sorption by Pinecone Derived Activated Carbon. Iran. J. Environ. Health Sci. Eng., 6 (4): 285-294.Setyowati, L. 1998. Pengaruh Penambahan Divinil Benzena (DVB) pada Kopolimerisasi Kationik Poli[eugenol-co-(divinil benzena)] dan Sifat Pertukaran Kation Kopoligaramnya (The Effect of divinylbenzene (DVB) Addition to Eugenol-DVB Cationic Copolymerization and Its Use As Cation-Exchanger), Thesis, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta, Indonesia.Shi, T.; Jia, S.; Chen, Y.; Wen, Y.; Du, C.; Guo, H.; Wang, Z. Adsorption of Pb(II), Cr(III), Cu(II), Cd(II) and Ni(II) onto a vanadium mine tailing from aqueous solution. J. Hazard. Mater. 2009, 169: 838-846, DOI: 10.1016/j.jhazmat.2009.04.020Sun, S.;Wang, A. Adsorption Kinetics of Cu(II) Ions Using N,O-Carboxymethyl-Chitosan. J. Hazard. Mater. 2006, B131: 103-111, DOI: 10.1016/j.jhazmat.2005.09.012Sun, S.; Wang, L.;Wang, A. Adsorption Properties of Crosslinked Carboxymethyl-chitosan Resin With Pb(II) as Template Ions. J. Hazard. Mater. 2006, B136: 930-937, DOI: 10.1016/j.jhazmat.2006.01.033Uzun, I.; Guzel, F. Adsorption of Some Heavy Metal Ions from Aqueous Solution by Activated Carbon and Comparison of Percent Adsorption Result of Activated Carbon with those of Some Other Adsorbents. Turk. J. Chem. 2000, 24: 291-297.Zou, X.; Pan, J.; Ou, H.; Wang, X.;Guan, W.; Li, C.; Yan, Y.; Duan, Y. Adsorptive removal of Cr(III) and Fe(III) from aqueous solution by chitosan/attapulgite composites: Equilibrium, thermodynamics and kinetics. Chem. Eng. J. 2011, 167: 112-121, DOI: 10.1016/j.cej.2010.12.009

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Speiseder, Thomas, Helga Hofmann-Sieber, Estefanía Rodríguez, Anna Schellenberg, Nuray Akyüz, Judith Dierlamm, Thilo Spruss, Claudia Lange et Thomas Dobner. « Efficient Transformation of Primary Human Mesenchymal Stromal Cells by Adenovirus Early Region 1 Oncogenes ». Journal of Virology 91, n^o 1 (19 octobre 2016). http://dx.doi.org/10.1128/jvi.01782-16.

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ABSTRACT Previous observations that human amniotic fluid cells (AFC) can be transformed by human adenovirus type 5 (HAdV-5) E1A/E1B oncogenes prompted us to identify the target cells in the AFC population that are susceptible to transformation. Our results demonstrate that one cell type corresponding to mesenchymal stem/stroma cells (hMSCs) can be reproducibly transformed by HAdV-5 E1A/E1B oncogenes as efficiently as primary rodent cultures. HAdV-5 E1-transformed hMSCs exhibit all properties commonly associated with a high grade of oncogenic transformation, including enhanced cell proliferation, anchorage-independent growth, increased growth rate, and high telomerase activity as well as numerical and structural chromosomal aberrations. These data confirm previous work showing that HAdV preferentially transforms cells of mesenchymal origin in rodents. More importantly, they demonstrate for the first time that human cells with stem cell characteristics can be completely transformed by HAdV oncogenes in tissue culture with high efficiency. Our findings strongly support the hypothesis that undifferentiated progenitor cells or cells with stem cell-like properties are highly susceptible targets for HAdV-mediated cell transformation and suggest that virus-associated tumors in humans may originate, at least in part, from infections of these cell types. We expect that primary hMSCs will replace the primary rodent cultures in HAdV viral transformation studies and are confident that these investigations will continue to uncover general principles of viral oncogenesis that can be extended to human DNA tumor viruses as well. IMPORTANCE It is generally believed that transformation of primary human cells with HAdV-5 E1 oncogenes is very inefficient. However, a few cell lines have been successfully transformed with HAdV-5 E1A and E1B, indicating that there is a certain cell type which is susceptible to HAdV-mediated transformation. Interestingly, all those cell lines have been derived from human embryonic tissue, albeit the exact cell type is not known yet. We show for the first time the successful transformation of primary human mesenchymal stromal cells (hMSCs) by HAdV-5 E1A and E1B. Further, we show upon HAdV-5 E1A and E1B expression that these primary progenitor cells exhibit features of tumor cells and can no longer be differentiated into the adipogenic, chondrogenic, or osteogenic lineage. Hence, primary hMSCs represent a robust and novel model system to elucidate the underlying molecular mechanisms of adenovirus-mediated transformation of multipotent human progenitor cells.

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King, Cason R., Steven F. Gameiro, Tanner M. Tessier, Ali Zhang et Joe S. Mymryk. « Mimicry of Cellular A Kinase-Anchoring Proteins Is a Conserved and Critical Function of E1A across Various Human Adenovirus Species ». Journal of Virology 92, n^o 8 (24 janvier 2018). http://dx.doi.org/10.1128/jvi.01902-17.

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ABSTRACTThe E1A proteins of the various human adenovirus (HAdV) species perform the critical task of converting an infected cell into a setting primed for virus replication. While E1A proteins differ in both sequence and mechanism, the evolutionary pressure on viruses with limited coding capacity ensures that these proteins often have significant overlap in critical functions. HAdV-5 E1A is known to use mimicry to rewire cyclic AMP (cAMP) signaling by decoupling protein kinase A (PKA) from cellular A kinase-anchoring proteins (AKAPs) and utilizing PKA to its own advantage. We show here that E1As from other species of HAdV also possess this viral AKAP (vAKAP) function and examine how they manipulate PKA. E1A from most species of HAdV examined contain a small AKAP-like motif in their N terminus which targets the docking-dimerization domain of PKA as the binding interface for a conserved protein-protein interaction. This motif is also responsible for an E1A-mediated relocalization of PKA regulatory subunits from the cytoplasm into the nucleus, with species-specific E1A proteins having preference for one particular isoform of PKA subunit over another. Importantly, we showed that these newly characterized vAKAPs can integrate into cAMP-responsive transcription as well as contribute to viral genome replication and infectious progeny production for several distinct HAdV species.IMPORTANCEThese data enhance the mechanistic knowledge on how HAdV E1A manipulates cellular PKA to benefit infection. The work establishes that mimicry of AKAPs and subversion of PKA-mediated cAMP signaling are conserved features for numerous human adenoviruses. This study also highlights the molecular determinants conferring selective protein-protein interactions between distinct PKA regulatory subunits and the different E1A proteins of these viruses. Additionally, it further emphasizes the utility of using viral proteins like E1A as tools for studying the molecular biology of cellular regulatory pathways.

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Graves, Drayson, Nikolas Akkerman, Scott Bachus et Peter Pelka. « Differential splicing of human adenovirus 5 E1A RNA expressed in cis versus in trans ». Journal of Virology, 23 décembre 2020. http://dx.doi.org/10.1128/jvi.02081-20.

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Human adenovirus (HAdV) is used extensively as a vector for gene delivery for a variety of purposes, including gene therapy and vaccine development. Most adenoviral vectors used for these approaches have the early region 1 (E1) deleted, which is complemented by the cell line. Most commonly these are 293 cells for HAdV serotype 2 or 5. The 293 cells have the left end of HAdV5 integrated into chromosome 19 and express the E1 genes and protein IX. We observed that viruses deleted for E1 region often grow poorly on 293 cells when compared to E1 wild-type viruses. Therefore, we investigated whether this is caused by splicing differences between E1A provided by the cell line, or in trans; and that provided by the infecting viral genome, or in cis. We observed that E1A RNA that was expressed from the genome of 293 cells was spliced differently during infection with an E1A-deleted dl312 virus, versus the same cells infected with dl309 or wt300. Importantly, 293 cells were not able to fully complement the late E1A transcripts, specifically 11S, 10S, and 9S that express E1A217R, E1A171R, and E1A55R isoforms respectively. We observed that these splicing differences likely arise due to different sub-nuclear localization of E1A RNA. E1A RNA expressed from the viral genome was localized to viral replication centers, while E1A RNA expressed from the cell’s genome was not. This loss of the late E1A mRNAs and their associated proteins impacts viral growth, gene expression, and protein levels. Complementation of the late E1A mRNAs in 293 cells restored some of the observed growth defect with dl312 and resulted in higher virus growth. IMPORTANCE Human adenovirus has become an important tool for medicine and research, and 293 cells and various other similar cell lines are used extensively for virus production where high viral yields are important. Such complementing cell lines are used for production of viral vectors and vaccines, which often have deletions and replacements in various viral genes. Deletions in essential genes, such as E1, are often complemented by the cell line that is used for virus propagation in trans. Here we show that even complete genetic complementation of a viral gene does not result in full protein complementation, which compromises virus growth. This is particularly important where high viral yields are crucial, such as in virus production for vaccine development or gene therapy.

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Molloy, David P., et Roger J. Grand. « Structural Determinants within the Adenovirus Early Region 1A Protein Spacer Region Necessary for Tumorigenesis ». Journal of Virology 94, n^o 21 (26 août 2020). http://dx.doi.org/10.1128/jvi.01268-20.

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ABSTRACT It has long been established that group A human adenoviruses (HAdV-A12, -A18, and -A31) can cause tumors in newborn rodents, with tumorigenicity related to the presence of a unique spacer region located between conserved regions 2 and 3 within the HAdV-A12 early region 1A (E1A) protein. Group B adenoviruses are weakly oncogenic, whereas most of the remaining human adenoviruses are nononcogenic. In an attempt to understand better the relationship between the structure of the AdE1A spacer region and oncogenicity of HAdVs, the structures of synthetic peptides identical or very similar to the adenovirus 12 E1A spacer region were determined and found to be α-helical using nuclear magnetic resonance (NMR) spectroscopy. This contrasts significantly with some previous suggestions that this region is unstructured. Using available predictive algorithms, the structures of spacer regions from other E1As were also examined, and the extent of the predicted α-helix was found to correlate reasonably well with the tumorigenicity of the respective virus. We suggest that this may represent an as-yet-unknown binding site for a partner protein required for tumorigenesis. IMPORTANCE This research analyzed small peptides equivalent to a region within the human adenovirus early region 1A protein that confers, in part, tumor-inducing properties to various degrees on several viral strains in rats and mice. The oncogenic spacer region is α-helical, which contrasts with previous suggestions that this region is unstructured. The helix is characterized by a stretch of amino acids rich in alanine residues that are organized into a hydrophobic, or “water-hating,” surface that is considered to form a major site of interaction with cellular protein targets that mediate tumor formation. The extent of α-helix in E1A from other adenovirus species can be correlated to a limited degree to the tumorigenicity of that virus. Some serotypes show significant differences in predicted structural propensity, suggesting that the amino acid type and physicochemical properties are also of importance.

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Omidi, Nahid, Azarakhsh Azaran, Manoochehr Makvandi, Gholamreza Khataminia, Kambiz Ahmadi Angali et Shahram Jalilian. « Characterization of the conserved regions of E1A protein from human adenovirus for reinforcement of cytotoxic T lymphocytes responses to the all genogroups causes ocular manifestation through an in silico approach ». Iranian Journal of Microbiology, 24 octobre 2022. http://dx.doi.org/10.18502/ijm.v14i5.10971.

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Background and Objectives: Adenovirus species B, C, D, and E are the most common causes of ocular manifestations caused by adenoviruses. FDA-approved treatment agents for adenovirus infections are not available. Cell-mediated im- munity is the major protective mechanism versus humanadenoviruses (HAdVs) infection and T cells specific for peptide epitopes from nonstructural proteins can prevent adenoviral dissemination. E1A CR2 regionof HAdVs Epitopes predicted for reinforcing cytotoxic T lymphocytes (CTLs) in the EKC patients. Among human adenoviruses E1 protein, four distinct E1Aregions had a significantly higher level of homology than the rest of E1A protein. E1A protein inhibits IFN signal trans- duction. Epitope-based vaccines aredesigned to have flexible and simple methods to synthesize a vaccine, using an adjuvant to trigger fast immune responses. CTL epitopes were applied to create amultiepitope vaccine. Conserve region1 (CR1) and CR3 have less antigenicity compared to CR2. Additionally, CR3 in HAdV-D8 contains three toxic areas. CR4 similar to the two regions CR1 and CR3 do not show acceptable antigenic properties. Materials and Methods: Bioinformatics’ tools were used to predict, refine and validate the 3D structure of the construct. Effective binding was predicted byprotein-protein docking of the epitope vaccine with MHC-I molecules and revealed the safety and efficacy of the predicted vaccine construct. Results: In silico analysis show that rising levels of cytotoxic CD8 + T cells, TH1 cells, macrophages, and neutrophils are linked to IFN-dominant TH1-type responses, which are detected in putative immune individuals. Conclusion: Combined with 3D protein modeling, this study predicted the epitopes of E1A CR2 protein in HAdVs.

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Krzywkowski, Tomasz, Sibel Ciftci, Farzaneh Assadian, Mats Nilsson et Tanel Punga. « Simultaneous Single-Cell In Situ Analysis of Human Adenovirus Type 5 DNA and mRNA Expression Patterns in Lytic and Persistent Infection ». Journal of Virology 91, n^o 11 (15 mars 2017). http://dx.doi.org/10.1128/jvi.00166-17.

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ABSTRACT An efficient adenovirus infection results in high-level accumulation of viral DNA and mRNAs in the infected cell population. However, the average viral DNA and mRNA content in a heterogeneous cell population does not necessarily reflect the same abundance in individual cells. Here, we describe a novel padlock probe-based rolling-circle amplification technique that enables simultaneous detection and analysis of human adenovirus type 5 (HAdV-5) genomic DNA and virus-encoded mRNAs in individual infected cells. We demonstrate that the method is applicable for detection and quantification of HAdV-5 DNA and mRNAs in short-term infections in human epithelial cells and in long-term infections in human B lymphocytes. Single-cell evaluation of these infections revealed high heterogeneity and unique cell subpopulations defined by differential viral DNA content and mRNA expression. Further, our single-cell analysis shows that the specific expression pattern of viral E1A 13S and 12S mRNA splice variants is linked to HAdV-5 DNA content in the individual cells. Furthermore, we show that expression of a mature form of the HAdV-5 histone-like protein VII affects virus genome detection in HAdV-5-infected cells. Collectively, padlock probes combined with rolling-circle amplification should be a welcome addition to the method repertoire for the characterization of the molecular details of the HAdV life cycle in individual infected cells. IMPORTANCE Human adenoviruses (HAdVs) have been extensively used as model systems to study various aspects of eukaryotic gene expression and genome organization. The vast majority of the HAdV studies are based on standard experimental procedures carried out using heterogeneous cell populations, where data averaging often masks biological differences. As every cell is unique, characteristics and efficiency of an HAdV infection can vary from cell to cell. Therefore, the analysis of HAdV gene expression and genome organization would benefit from a method that permits analysis of individual infected cells in the heterogeneous cell population. Here, we show that the padlock probe-based rolling-circle amplification method can be used to study concurrent viral DNA accumulation and mRNA expression patterns in individual HAdV-5-infected cells. Hence, this versatile method can be applied to detect the extent of infection and virus gene expression changes in different HAdV-5 infections.

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King, Cason R., Tanner M. Tessier, Mackenzie J. Dodge, Jason B. Weinberg et Joe S. Mymryk. « Inhibition of Human Adenovirus Replication by the Importin α/β1 Nuclear Import Inhibitor Ivermectin ». Journal of Virology 94, n^o 18 (8 juillet 2020). http://dx.doi.org/10.1128/jvi.00710-20.

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ABSTRACT Human adenoviruses (HAdV) are ubiquitous within the human population and comprise a significant burden of respiratory illnesses worldwide. Pediatric and immunocompromised individuals are at particular risk for developing severe disease; however, no approved antiviral therapies specific to HAdV exist. Ivermectin is an FDA-approved broad-spectrum antiparasitic drug that also exhibits antiviral properties against a diverse range of viruses. Its proposed function is inhibiting the classical protein nuclear import pathway mediated by importin-α (Imp-α) and -β1 (Imp-β1). Many viruses, including HAdV, rely on this host pathway for transport of viral proteins across the nuclear envelope. In this study, we show that ivermectin inhibits HAdV-C5 early gene transcription, early and late protein expression, genome replication, and production of infectious viral progeny. Similarly, ivermectin inhibits genome replication of HAdV-B3, a clinically important pathogen responsible for numerous recent outbreaks. Mechanistically, we show that ivermectin disrupts binding of the viral E1A protein to Imp-α without affecting the interaction between Imp-α and Imp-β1. Our results further extend ivermectin’s broad antiviral activity and provide a mechanistic underpinning for its mode of action as an inhibitor of cellular Imp-α/β1-mediated nuclear import. IMPORTANCE Human adenoviruses (HAdVs) represent a ubiquitous and clinically important pathogen without an effective antiviral treatment. HAdV infections typically cause mild symptoms; however, individuals such as children, those with underlying conditions, and those with compromised immune systems can develop severe disseminated disease. Our results demonstrate that ivermectin, an FDA-approved antiparasitic agent, is effective at inhibiting replication of several HAdV types in vitro. This is in agreement with the growing body of literature suggesting ivermectin has broad antiviral activity. This study expands our mechanistic knowledge of ivermectin by showing that ivermectin targets the ability of importin-α (Imp-α) to recognize nuclear localization sequences, without effecting the Imp-α/β1 interaction. These data also exemplify the applicability of targeting host factors upon which viruses rely as a viable antiviral strategy.

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Saha, Bratati, et Robin J. Parks. « Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Suppresses Human Adenovirus Gene Expression and Replication ». Journal of Virology 93, n^o 12 (3 avril 2019). http://dx.doi.org/10.1128/jvi.00088-19.

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ABSTRACTHuman adenovirus (HAdV) causes minor illnesses in most patients but can lead to severe disease and death in pediatric, geriatric, and immunocompromised individuals. No approved antiviral therapy currently exists for the treatment of these severe HAdV-induced diseases. In this study, we show that the pan-histone deacetylase (HDAC) inhibitor SAHA reduces HAdV-5 gene expression and DNA replication in tissue culture, ultimately decreasing virus yield from infected cells. Importantly, SAHA also reduced gene expression from more virulent and clinically relevant serotypes, including HAdV-4 and HAdV-7. In addition to SAHA, several other HDAC inhibitors (e.g., trichostatin A, apicidin, and panobinostat) also affected HAdV gene expression. We determined that loss of class I HDAC activity, mainly HDAC2, impairs efficient expression of viral genes, and that E1A physically interacts with HDAC2. Our results suggest that HDAC activity is necessary for HAdV replication, which may represent a novel pharmacological target in HAdV-induced disease.IMPORTANCEAlthough human adenovirus (HAdV) can cause severe diseases that can be fatal in some populations, there are no effective treatments to combat HAdV infection. In this study, we determined that the pan-histone deacetylase (HDAC) inhibitor SAHA has inhibitory activity against several clinically relevant serotypes of HAdV. This U.S. Food and Drug Administration-approved compound affects various stages of the virus lifecycle and reduces virus yield even at low concentrations. We further report that class I HDAC activity, particularly HDAC2, is required for efficient expression of viral genes during lytic infection. Investigation of the mechanism underlying SAHA-mediated suppression of HAdV gene expression and replication will enhance current knowledge of virus-cell interaction and may aid in the development of more effective antivirals with lower toxicity for the treatment of HAdV infections.

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Bair, Camden R., Wei Zhang, Gabriel Gonzalez, Arash Kamali, Daniel Stylos, Jorge C. G. Blanco et Adriana E. Kajon. « HUMAN ADENOVIRUS TYPE 4 COMPRISES TWO MAJOR PHYLOGROUPS WITH DISTINCT REPLICATIVE FITNESS AND VIRULENCE PHENOTYPES ». Journal of Virology, 7 juillet 2021. http://dx.doi.org/10.1128/jvi.01090-21.

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Human adenovirus type 4 (HAdV-E4) is the only type (and serotype) classified within species Human mastadenovirus E that has been isolated from a human host to the present. Recent phylogenetic analysis of whole genome sequences of strains representing the spectrum of intratypic genetic diversity described to date identified two major evolutionary lineages designated phylogroups (PG) I, and II, and validated the early clustering of HAdV-E4 genomic variants into two major groups by low resolution restriction fragment length polymorphism analysis. In this study we expanded our original analysis of intra- and inter-PG genetic variability, and used a panel of viruses representative of the spectrum of genetic diversity described for HAdV-E4 to examine the magnitude of inter- and intra-PG phenotypic diversity using an array of cell-based assays and a cotton rat model of HAdV respiratory infection. Our proteotyping of HAdV-E strains using concatenated protein sequences in selected coding regions including E1A, E1B-19K and -55K, DNA polymerase, L4-100K, various E3 proteins, and E4-34K confirmed that the two clades encode distinct variants/proteotypes at most of these loci. Our in vitro and in vivo studies demonstrated that PG I and PG II differ in their growth, spread, and cell killing phenotypes in cell culture and in their pulmonary pathogenic phenotypes. Surprisingly, the differences in replicative fitness documented in vitro between PGs did not correlate with the differences in virulence observed in the cotton rat model. This body of work is the first reporting phenotypic correlates of naturally occurring intratypic genetic variability for HAdV-E4. IMPORTANCE Human adenovirus type 4 (HAdV-E4) is a prevalent causative agent of acute respiratory illness of variable severity and of conjunctivitis and comprises two major phylogroups that carry distinct coding variations in proteins involved in viral replication and modulation of host responses to infection. Our data show that PG I and PG II are intrinsically different regarding their ability to grow and spread in culture and to cause pulmonary disease in cotton rats. This is the first report of phenotypic divergence among naturally occurring known genetic variants of a HAdV type of medical importance. This research reveals readily detectable phenotypic differences between strains representing phylogroups I and II, and it introduces a unique experimental system for the elucidation of the genetic basis of adenovirus fitness and virulence and thus for increasing our understanding of the implications of intratypic genetic diversity in the presentation and course of HAdV-E4-associated disease.

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Samantaray, Mr Utkalendu Suvendusekhar, et Ms Piyanki Santra. « Human Adenovirus Serotypes Efficiently Transducing HEK293 Cells : An In Vitro Propagation of HAdv ». International Journal for Research in Applied Sciences and Biotechnology 8, n^o 5 (8 septembre 2021). http://dx.doi.org/10.31033/ijrasb.8.5.3.

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Generally, a gene which is inserted directly into a cell does not operate independently. Instead, the transmission of the gene is genetically modified by a biological messenger called a vector, consists of a transgene and a large DNA sequence as a backbone. Since they can deliver the new gene by infecting the cell, such viruses are also used as vectors. The adenovirus is a non-enveloped virus that can be tailored to transfer DNA to target cells, and it has sparked a lot of interest in the field, particularly in clinical trial therapy techniques. For the new age production of COVID-19 vaccine, development of different mammalian cell lines like HEK293 (most reliable growth and prosperity for transfection) and recombinant adenoviral vectors have become the first priority for biopharmaceutical giants and globally approved vaccine manufacturers to scale up their vaccine production. Adenoviruses have an icosahedral shape, with a protein coat encasing the viral double-stranded DNA genome. Because the adenovirus genome is relatively small, it's a good candidate for insertion of foreign DNA. The adenovirus E1A gene is deleted, and the virus loses its capacity to replicate. This ability can be restored during cell culture propagation by employing cells that produce the E1A protein, for example. Hence, in this mini research, I have shared an overview of the propagation of adenoviral vectors, i.e. recombinant adenovirus SARS CoV-2 vector in HEK-293 cell suspension culture.

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Grosso, Filomena, Peter Stoilov, Clifford Lingwood, Martha Brown et Alan Cochrane. « Suppression of Adenovirus Replication by Cardiotonic Steroids ». Journal of Virology 91, n^o 3 (23 novembre 2016). http://dx.doi.org/10.1128/jvi.01623-16.

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ABSTRACT The dependence of adenovirus on the host pre-RNA splicing machinery for expression of its complete genome potentially makes it vulnerable to modulators of RNA splicing, such as digoxin and digitoxin. Both drugs reduced the yields of four human adenoviruses (HAdV-A31, -B35, and -C5 and a species D conjunctivitis isolate) by at least 2 to 3 logs by affecting one or more steps needed for genome replication. Immediate early E1A protein levels are unaffected by the drugs, but synthesis of the delayed protein E4orf6 and the major late capsid protein hexon is compromised. Quantitative reverse transcription-PCR (qRT-PCR) analyses revealed that both drugs altered E1A RNA splicing (favoring the production of 13S over 12S RNA) early in infection and partially blocked the transition from 12S and 13S to 9S RNA at late stages of virus replication. Expression of multiple late viral protein mRNAs was lost in the presence of either drug, consistent with the observed block in viral DNA replication. The antiviral effect was dependent on the continued presence of the drug and was rapidly reversible. RIDK34, a derivative of convallotoxin, although having more potent antiviral activity, did not show an improved selectivity index. All three drugs reduced metabolic activity to some degree without evidence of cell death. By blocking adenovirus replication at one or more steps beyond the onset of E1A expression and prior to genome replication, digoxin and digitoxin show potential as antiviral agents for treatment of serious adenovirus infections. Furthermore, understanding the mechanism(s) by which digoxin and digitoxin inhibit adenovirus replication will guide the development of novel antiviral therapies. IMPORTANCE Despite human adenoviruses being a common and, in some instances, life-threating pathogen in humans, there are few well-tolerated therapies. In this report, we demonstrate that two cardiotonic steroids already in use in humans, digoxin and digitoxin, are potent inhibitors of multiple adenovirus species. A synthetic derivative of the cardiotonic steroid convallotoxin was even more potent than digoxin and digitoxin when tested with HAdV-C5. These drugs alter the cascade of adenovirus gene expression, acting after initiation of early gene expression to block viral DNA replication and synthesis of viral structural proteins. These findings validate a novel approach to treating adenovirus infections through the modulation of host cell processes.

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Kolbe, Viktoria, Wing H. Ip, Lisa Kieweg-Thompson, Judith Lang, Julia Gruhne, Tina Meyer, Britta Wilkens et al. « Conserved E1B-55K SUMOylation in Different Human Adenovirus Species Is a Potent Regulator of Intracellular Localization ». Journal of Virology 96, n^o 3 (9 février 2022). http://dx.doi.org/10.1128/jvi.00838-21.

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E1B-55K is a multifunctional adenoviral protein and its functions are highly regulated by SUMOylation. Although functional consequences of SUMOylated HAdV-C5 E1B-55K are well studied, we lack information on the effects of SUMOylation on homologous E1B-55K proteins from other HAdV species.

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Menon, Balaraj B., Xiaohong Zhou, Sandra Spurr-Michaud, Jaya Rajaiya, James Chodosh et Ilene K. Gipson. « Epidemic Keratoconjunctivitis-Causing Adenoviruses Induce MUC16 Ectodomain Release To Infect Ocular Surface Epithelial Cells ». mSphere 1, n^o 1 (10 février 2016). http://dx.doi.org/10.1128/msphere.00112-15.

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ABSTRACT Human adenoviruses (HAdVs) are double-stranded DNA viruses that cause infections across all mucosal tissues in the body. At the ocular surface, HAdVs cause keratoconjunctivitis (E. Ford, K. E. Nelson, and D. Warren, Epidemiol Rev 9:244–261, 1987, and C. M. Robinson, D. Seto, M. S. Jones, D. W. Dyer, and J. Chodosh, Infect Genet Evol 11:1208–1217, 2011, doi:10.1016/j.meegid.2011.04.031)—a highly contagious infection that accounts for nearly 60% of conjunctivitis cases in the United States (R. P. Sambursky, N. Fram, and E. J. Cohen, Optometry 78:236–239, 2007, doi:10.1016/j.optm.2006.11.012, and A. M. Pihos, J Optom 6:69–74, 2013, doi:10.1016/j.optom.2012.08.003). The infection begins with HAdV entry within ocular surface epithelial cells; however, the mechanisms used by HAdVs to transit the otherwise protective mucosal barrier of ocular surface epithelial cells prior to entry remain unknown. Here, we report that the highly virulent keratoconjunctivitis-causing HAdV-D37 induces release of the extracellular domain (ectodomain) of MUC16, a major component of the mucosal barrier of ocular surface epithelial cells, prior to infecting underlying cells. Currently, there is no specific treatment for controlling this infection. Understanding the early steps involved in the pathogenesis of keratoconjunctivitis and using this information to intercept adenoviral entry within cells may guide the development of novel strategies for controlling the infection. Human adenoviruses (HAdV), species D in particular (HAdV-D), are frequently associated with epidemic keratoconjunctivitis (EKC). Although the infection originates at the ocular surface epithelium, the mechanisms by which HAdV-Ds bypass the membrane-associated mucin (MAM)-rich glycocalyx of the ocular surface epithelium to trigger infection and inflammation remain unknown. Here, we report that an EKC-causing adenovirus (HAdV-D37), but not a non-EKC-causing one (HAdV-D19p), induces ectodomain release of MUC16—a MAM with barrier functions at the ocular surface—from cultured human corneal and conjunctival epithelial cells. HAdV-D37, but not HAdV-D19p, is also found to decrease the glycocalyx barrier function of corneal epithelial cells, as determined by rose bengal dye penetrance assays. Furthermore, results from quantitative PCR (qPCR) amplification of viral genomic DNA using primers specific to a conserved region of the E1B gene show that, in comparison to infection by HAdV-D19p, infection by HAdV-D37 is significantly increased in corneal epithelial cells. Collectively, these results point to a MUC16 ectodomain release-dependent mechanism utilized by the EKC-causing HAdV-D37 to initiate infection at the ocular surface. These findings are important in terms of understanding the pathogenesis of adenoviral keratoconjunctivitis. Similar MAM ectodomain release mechanisms may be prevalent across other mucosal epithelia in the body (e.g., the airway epithelium) that are prone to adenoviral infection. IMPORTANCE Human adenoviruses (HAdVs) are double-stranded DNA viruses that cause infections across all mucosal tissues in the body. At the ocular surface, HAdVs cause keratoconjunctivitis (E. Ford, K. E. Nelson, and D. Warren, Epidemiol Rev 9:244–261, 1987, and C. M. Robinson, D. Seto, M. S. Jones, D. W. Dyer, and J. Chodosh, Infect Genet Evol 11:1208–1217, 2011, doi:10.1016/j.meegid.2011.04.031)—a highly contagious infection that accounts for nearly 60% of conjunctivitis cases in the United States (R. P. Sambursky, N. Fram, and E. J. Cohen, Optometry 78:236–239, 2007, doi:10.1016/j.optm.2006.11.012, and A. M. Pihos, J Optom 6:69–74, 2013, doi:10.1016/j.optom.2012.08.003). The infection begins with HAdV entry within ocular surface epithelial cells; however, the mechanisms used by HAdVs to transit the otherwise protective mucosal barrier of ocular surface epithelial cells prior to entry remain unknown. Here, we report that the highly virulent keratoconjunctivitis-causing HAdV-D37 induces release of the extracellular domain (ectodomain) of MUC16, a major component of the mucosal barrier of ocular surface epithelial cells, prior to infecting underlying cells. Currently, there is no specific treatment for controlling this infection. Understanding the early steps involved in the pathogenesis of keratoconjunctivitis and using this information to intercept adenoviral entry within cells may guide the development of novel strategies for controlling the infection.

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Müncheberg, Sarah, Ron T. Hay, Wing H. Ip, Tina Meyer, Christina Weiß, Jara Brenke, Sawinee Masser, Kamyar Hadian, Thomas Dobner et Sabrina Schreiner. « E1B-55K-Mediated Regulation of RNF4 SUMO-Targeted Ubiquitin Ligase Promotes Human Adenovirus Gene Expression ». Journal of Virology 92, n^o 13 (25 avril 2018). http://dx.doi.org/10.1128/jvi.00164-18.

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ABSTRACTHuman adenovirus (HAdV) E1B-55K is a multifunctional regulator of productive viral replication and oncogenic transformation in nonpermissive mammalian cells. These functions depend on E1B-55K's posttranslational modification with the SUMO protein and its binding to HAdV E4orf6. Both early viral proteins recruit specific host factors to form an E3 ubiquitin ligase complex that targets antiviral host substrates for proteasomal degradation. Recently, we reported that the PML-NB-associated factor Daxx represses efficient HAdV productive infection and is proteasomally degraded via a SUMO-E1B-55K-dependent, E4orf6-independent pathway, the details of which remained to be established. RNF4, a cellular SUMO-targeted ubiquitin ligase (STUbL), induces ubiquitinylation of specific SUMOylated proteins and plays an essential role during DNA repair. Here, we show that E1B-55K recruits RNF4 to the insoluble nuclear matrix fraction of the infected cell to support RNF4/Daxx association, promoting Daxx PTM and thus inhibiting this antiviral factor. Removing RNF4 from infected cells using RNA interference resulted in blocking the proper establishment of viral replication centers and significantly diminished viral gene expression. These results provide a model for how HAdV antagonize the antiviral host responses by exploiting the functional capacity of cellular STUbLs. Thus, RNF4 and its STUbL function represent a positive factor during lytic infection and a novel candidate for future therapeutic antiviral intervention strategies.IMPORTANCEDaxx is a PML-NB-associated transcription factor that was recently shown to repress efficient HAdV productive infection. To counteract this antiviral measurement during infection, Daxx is degraded via a novel pathway including viral E1B-55K and host proteasomes. This virus-mediated degradation is independent of the classical HAdV E3 ubiquitin ligase complex, which is essential during viral infection to target other host antiviral substrates. To maintain a productive viral life cycle, HAdV E1B-55K early viral protein inhibits the chromatin-remodeling factor Daxx in a SUMO-dependent manner. In addition, viral E1B-55K protein recruits the STUbL RNF4 and sequesters it into the insoluble fraction of the infected cell. E1B-55K promotes complex formation between RNF4- and E1B-55K-targeted Daxx protein, supporting Daxx posttranslational modification prior to functional inhibition. Hence, RNF4 represents a novel host factor that is beneficial for HAdV gene expression by supporting Daxx counteraction. In this regard, RNF4 and other STUbL proteins might represent novel targets for therapeutic intervention.

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Jung, Sang Hoon, Nami Han et Mi ja Eom. « Co-occurrence of Marchiafava-Bignami Disease and Alcoholic Polyneuropathy in Chronic Alcoholic Patient Who Had Past History of Wernicke Encephalopathy : a Case Report ». Brain & ; Neurorehabilitation 14, n^o 2 (2021). http://dx.doi.org/10.12786/bn.2021.14.e19.

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Reichel, Anna, Anne-Charlotte Stilp, Myriam Scherer, Nina Reuter, Sören Lukassen, Bahram Kasmapour, Sabrina Schreiner, Luka Cicin-Sain, Andreas Winterpacht et Thomas Stamminger. « Chromatin-Remodeling Factor SPOC1 Acts as a Cellular Restriction Factor against Human Cytomegalovirus by Repressing the Major Immediate Early Promoter ». Journal of Virology 92, n^o 14 (9 mai 2018). http://dx.doi.org/10.1128/jvi.00342-18.

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ABSTRACTThe cellular protein SPOC1 (survival time-associated PHD [plant homeodomain] finger protein in ovarian cancer 1) acts as a regulator of chromatin structure and the DNA damage response. It binds H3K4me2/3-containing chromatin and promotes DNA condensation by recruiting corepressors such as KAP-1 and H3K9 methyltransferases. Previous studies identified SPOC1 as a restriction factor against human adenovirus (HAdV) infection that is antagonized by E1B-55K/E4-orf6-dependent proteasomal degradation. Here, we demonstrate that, in contrast to HAdV-infected cells, SPOC1 is transiently upregulated during the early phase of human cytomegalovirus (HCMV) replication. We show that the expression of immediate early protein 1 (IE1) is sufficient and necessary to induce SPOC1. Additionally, we discovered that during later stages of infection, SPOC1 is downregulated in a glycogen synthase kinase 3β (GSK-3β)-dependent manner. We provide evidence that SPOC1 overexpression severely impairs HCMV replication by repressing the initiation of viral immediate early (IE) gene expression. Consistently, we observed that SPOC1-depleted primary human fibroblasts displayed an augmented initiation of viral IE gene expression. This occurs in a multiplicity of infection (MOI)-dependent manner, a defining hallmark of intrinsic immunity. Interestingly, repression requires the presence of high SPOC1 levels at the start of infection, while later upregulation had no negative impact, suggesting distinct temporal roles of SPOC1 during the HCMV replicative cycle. Mechanistically, we observed a highly specific association of SPOC1 with the major immediate early promoter (MIEP), strongly suggesting that SPOC1 inhibits HCMV replication by MIEP binding and the subsequent recruitment of heterochromatin-building factors. Thus, our data add SPOC1 as a novel factor to the endowment of a host cell to restrict cytomegalovirus infections.IMPORTANCEAccumulating evidence indicates that during millennia of coevolution, host cells have developed a sophisticated compilation of cellular factors to restrict cytomegalovirus infections. Defining this equipment is important to understand cellular barriers against viral infection and to develop strategies to utilize these factors for antiviral approaches. So far, constituents of PML nuclear bodies and interferon gamma-inducible protein 16 (IFI16) were known to mediate intrinsic immunity against HCMV. In this study, we identify the chromatin modulator SPOC1 as a novel restriction factor against HCMV. We show that preexisting high SPOC1 protein levels mediate a silencing of HCMV gene expression via a specific association with an important viralcis-regulatory element, the major immediate early promoter. Since SPOC1 expression varies between cell types, this factor may play an important role in tissue-specific defense against HCMV.

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