SUBGENOMIC RNA OF ARENAVIRUS PICHINDE AND ITS IMPLICATION IN REGULATION OF VIRAL GENE EXPRESSION IN PRODUCTIVE INFECTION AND PERSISTENCE

Abstract Human cytomegalovirus (HCMV) is a widespread obligatory human pathogen causing life-threatening disease in immunocompromised hosts. Myeloid cells such as monocyte-derived dendritic cells (moDCs) are targets of HCMV. Here, we performed single-cell RNA sequencing, which revealed infection of most moDCs upon in vitro HCMV exposure, whereas only a fraction of them initiated viral gene expression. We identified three moDC subsets, of which CD1a−/CD86− cells showed the highest susceptibility. Upon HCMV entry, STING activation not only induced IFN-β, but also promoted viral gene expression. Upon progression of infection, IFN-β but not IFN-λ1 expression was inhibited. Similarly, ISG expression was initially induced and then shut off and thus allowed productive infection. Increased viral gene expression was associated with the induction of several pro- (RHOB, HSP1A1, DNAJB1) and anti-viral (RNF213, TNFSF10, IFI16) genes. Thus, moDC permissiveness to HCMV depends on complex interactions between virus sensing, regulation of IFNs/ISGs and viral gene expression.

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Chromatin Modulation of Herpesvirus Lytic Gene Expression: Managing Nucleosome Density and Heterochromatic Histone Modifications

mBio ◽

10.1128/mbio.00098-16 ◽

2016 ◽

Vol 7 (1) ◽

Cited By ~ 4

Author(s):

Thomas M. Kristie

Keyword(s):

Gene Expression ◽

Histone Modifications ◽

Viral Gene Expression ◽

Virus Genome ◽

Early Gene ◽

Productive Infection ◽

Viral Gene ◽

Early Protein ◽

Protein Icp0 ◽

Simplex Virus

ABSTRACT Like their cellular hosts, herpesviruses are subject to the regulatory impacts of chromatin assembled on their genomes. Upon infection, these viruses are assembled into domains of chromatin with heterochromatic signatures that suppress viral gene expression or euchromatic characteristics that promote gene expression. The organization and modulation of these chromatin domains appear to be intimately linked to the coordinated expression of the different classes of viral genes and thus ultimately play an important role in the progression of productive infection or the establishment and maintenance of viral latency. A recent report from the Knipe laboratory (J. S. Lee, P. Raja, and D. M. Knipe, mBio 7:e02007-15, 2016) contributes to the understanding of the dynamic modulation of chromatin assembled on the herpes simplex virus genome by monitoring the levels of characteristic heterochromatic histone modifications (histone H3 lysine 9 and 27 methylation) associated with a model viral early gene during the progression of lytic infection. Additionally, this study builds upon previous observations that the viral immediate-early protein ICP0 plays a role in reducing the levels of heterochromatin associated with the early genes.

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The bovine herpesvirus 1 gene encoding infected cell protein 0 (bICP0) can inhibit interferon-dependent transcription in the absence of other viral genes

Journal of General Virology ◽

10.1099/vir.0.81109-0 ◽

2005 ◽

Vol 86 (10) ◽

pp. 2697-2702 ◽

Cited By ~ 40

Author(s):

Gail Henderson ◽

Yange Zhang ◽

Clinton Jones

Keyword(s):

Gene Expression ◽

Ring Finger ◽

Viral Gene Expression ◽

Bovine Herpesvirus ◽

Productive Infection ◽

Cell Protein ◽

Viral Gene ◽

Bovine Herpesvirus 1 ◽

Infected Cell Protein ◽

Herpesvirus 1

The infected cell protein 0 (bICP0) encoded by Bovine herpesvirus 1 (BHV-1) stimulates viral gene expression and productive infection. As bICP0 is expressed constitutively during productive infection, it is considered to be the major viral regulatory protein. Like other alphaherpesvirus ICP0 homologues, bICP0 contains a zinc RING finger near its N terminus that activates transcription and regulates subcellular localization. In this study, evidence is provided that bICP0 represses the human beta interferon (IFN-β) promoter and a simple promoter with consensus IFN-stimulated response elements following stimulation with double-stranded RNA (polyinosinic–polycytidylic acid), IFN regulatory factor 3 (IRF3) or IRF7. bICP0 also inhibits the ability of two protein kinases (TBK1 and IKKε) to activate IFN-β promoter activity. The zinc RING finger is necessary for inhibiting IFN-dependent transcription in certain cell types. Collectively, these studies suggest that bICP0 activates productive infection by stimulating viral gene expression and inhibiting IFN-dependent transcription.

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Posttranscriptional Suppression of Interleukin-6 Production by Human Cytomegalovirus

Journal of Virology ◽

10.1128/jvi.79.1.472-485.2005 ◽

2005 ◽

Vol 79 (1) ◽

pp. 472-485 ◽

Cited By ~ 33

Author(s):

Claire Gealy ◽

Marian Denson ◽

Christine Humphreys ◽

Brian McSharry ◽

Gavin Wilkinson ◽

...

Keyword(s):

Gene Expression ◽

Human Cytomegalovirus ◽

Transcriptional Activation ◽

Interleukin 6 ◽

Human Fibroblasts ◽

Intracellular Localization ◽

Viral Gene Expression ◽

Suppressive Effect ◽

Productive Infection ◽

Viral Gene

ABSTRACT Human cytomegalovirus (HCMV) has evolved multiple strategies for suppression of the antiviral response of the infected cell. DNA array technology has revealed that HCMV clearly regulates host gene expression during the course of a productive infection by enhancing, sustaining, or suppressing steady-state levels of cellular transcripts. Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a central role in the immune response to infection. Here we report a detailed study of the effects of HCMV infection on IL-6 expression by human fibroblasts. UV-inactivated virus was found to induce high levels of IL-6 mRNA and protein expression, and IL-6 mRNA remained abundant in cells 16 h after inoculation even though the level of ongoing IL-6 transcription was not significantly enhanced. In lytic HCMV infections, the onset of viral gene expression resulted in two apparently antagonistic effects on IL-6 expression: (i) transcriptional activation, mediated at least in part by the IE2p86 protein, and (ii) posttranscriptional suppression mediated by destabilization of IL-6 mRNA. Transcriptional activation was outweighed by the suppressive effect, such that cells undergoing productive infection produced less IL-6 than cells challenged with inactivated virus. Suppression of IL-6 expression was independent of the viral IL-10 homologue, cmvIL-10. Destabilization of IL-6 mRNA was observed to coincide with the enhanced expression and aberrant intracellular localization of HuR, an mRNA-binding protein known to interact with IL-6 and other mRNAs containing 3′ AU-rich elements. Our data suggest a novel mechanism for gene regulation by HCMV at the posttranscriptional level.

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Respiratory Syncytial Virus Infects and Abortively Replicates in the Lungs in Spite of Preexisting Immunity

Journal of Virology ◽

10.1128/jvi.00102-07 ◽

2007 ◽

Vol 81 (17) ◽

pp. 9443-9450 ◽

Cited By ~ 38

Author(s):

Marina S. Boukhvalova ◽

Gregory A. Prince ◽

Jorge C. G. Blanco

Keyword(s):

Gene Expression ◽

Respiratory Syncytial Virus ◽

Viral Gene Expression ◽

The Elderly ◽

Productive Infection ◽

Viral Gene ◽

Rna Transcripts ◽

Rsv Infection ◽

Syncytial Virus

ABSTRACT Respiratory syncytial virus (RSV) is a major cause of bronchiolitis and viral pneumonia in young children and a serious health risk in immunocompromised individuals and the elderly. Immunity to RSV is not completely understood. In this work, we established a method for monitoring RSV infection by real-time PCR and applied this method for analysis of RSV replication in vivo in the cotton rat model in naïve animals and in animals rendered immune to RSV by prior RSV infection. We found that even though no virus could be isolated from the lungs of RSV-challenged immune animals, RSV infection in fact took place and an accumulation of viral RNA transcripts was observed. This type of replication, therefore, can be termed “abortive,” as RSV is capable of entering the cells in the lungs of immune animals, yet the production of progeny viruses is impaired. Similar patterns of RSV gene expression gradient were observed between naïve and reinfected animals, indicating that the skewing of mRNA gradient of viral gene expression, a mechanism documented during latent infection by other viruses, is not likely to be responsible for abortive replication of RSV during reinfection. We found that passive administration of antibodies to RSV prevents productive infection normally accompanied by viral release in the lung, but it does not prevent abortive replication of the virus. To the best of our knowledge, this is the first evidence of abortive replication of RSV in vivo.

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NAD-linked mechanisms of gene de-repression and a novel role for CtBP in persistent adenovirus infection of lymphocytes

Virology Journal ◽

10.1186/s12985-019-1265-y ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 1

Author(s):

Megan L. Dickherber ◽

Charlie Garnett-Benson

Keyword(s):

Gene Expression ◽

Epithelial Cells ◽

Cell Lines ◽

Lymphocyte Activation ◽

Viral Gene Expression ◽

Productive Infection ◽

Viral Gene ◽

Global Changes ◽

Persistently Infected ◽

Infected Cells

Abstract Background Adenovirus (AdV) infection is ubiquitous in the human population and causes acute infection in the respiratory and gastrointestinal tracts. In addition to lytic infections in epithelial cells, AdV can persist in a latent form in mucosal lymphocytes, and nearly 80% of children contain viral DNA in the lymphocytes of their tonsils and adenoids. Reactivation of latent AdV is thought to be the source of deadly viremia in pediatric transplant patients. Adenovirus latency and reactivation in lymphocytes is not well studied, though immune cell activation has been reported to promote productive infection from latency. Lymphocyte activation induces global changes in cellular gene expression along with robust changes in metabolic state. The ratio of free cytosolic NAD+/NADH can impact gene expression via modulation of transcriptional repressor complexes. The NAD-dependent transcriptional co-repressor C-terminal Binding Protein (CtBP) was discovered 25 years ago due to its high affinity binding to AdV E1A proteins, however, the role of this interaction in the viral life cycle remains unclear. Methods The dynamics of persistently- and lytically-infected cells are evaluated. RT-qPCR is used to evaluate AdV gene expression following lymphocyte activation, treatment with nicotinamide, or disruption of CtBP-E1A binding. Results PMA and ionomycin stimulation shifts the NAD+/NADH ratio in lymphocytic cell lines and upregulates viral gene expression. Direct modulation of NAD+/NADH by nicotinamide treatment also upregulates early and late viral transcripts in persistently-infected cells. We found differential expression of the NAD-dependent CtBP protein homologs between lymphocytes and epithelial cells, and inhibition of CtBP complexes upregulates AdV E1A expression in T lymphocyte cell lines but not in lytically-infected epithelial cells. Conclusions Our data provide novel insight into factors that can regulate AdV infections in activated human lymphocytes and reveal that modulation of cellular NAD+/NADH can de-repress adenovirus gene expression in persistently-infected lymphocytes. In contrast, disrupting the NAD-dependent CtBP repressor complex interaction with PxDLS-containing binding partners paradoxically alters AdV gene expression. Our findings also indicate that CtBP activities on viral gene expression may be distinct from those occurring upon metabolic alterations in cellular NAD+/NADH ratios or those occurring after lymphocyte activation.

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Molecular biology of human papillomavirus infection and cervical cancer

Clinical Science ◽

10.1042/cs20050369 ◽

2006 ◽

Vol 110 (5) ◽

pp. 525-541 ◽

Cited By ~ 552

Author(s):

John Doorbar

Keyword(s):

Gene Expression ◽

High Risk ◽

Viral Gene Expression ◽

Cervical Neoplasia ◽

Productive Infection ◽

Viral Gene ◽

Low Grade ◽

Cervical Cancers ◽

Hpv Types ◽

High Risk Hpv

HPVs (human papillomaviruses) infect epithelial cells and cause a variety of lesions ranging from common warts/verrucas to cervical neoplasia and cancer. Over 100 different HPV types have been identified so far, with a subset of these being classified as high risk. High-risk HPV DNA is found in almost all cervical cancers (>99.7%), with HPV16 being the most prevalent type in both low-grade disease and cervical neoplasia. Productive infection by high-risk HPV types is manifest as cervical flat warts or condyloma that shed infectious virions from their surface. Viral genomes are maintained as episomes in the basal layer, with viral gene expression being tightly controlled as the infected cells move towards the epithelial surface. The pattern of viral gene expression in low-grade cervical lesions resembles that seen in productive warts caused by other HPV types. High-grade neoplasia represents an abortive infection in which viral gene expression becomes deregulated, and the normal life cycle of the virus cannot be completed. Most cervical cancers arise within the cervical transformation zone at the squamous/columnar junction, and it has been suggested that this is a site where productive infection may be inefficiently supported. The high-risk E6 and E7 proteins drive cell proliferation through their association with PDZ domain proteins and Rb (retinoblastoma), and contribute to neoplastic progression, whereas E6-mediated p53 degradation prevents the normal repair of chance mutations in the cellular genome. Cancers usually arise in individuals who fail to resolve their infection and who retain oncogene expression for years or decades. In most individuals, immune regression eventually leads to clearance of the virus, or to its maintenance in a latent or asymptomatic state in the basal cells.

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Combinatorial Effects of the Glucocorticoid Receptor and Krüppel-Like Transcription Factor 15 on Bovine Herpesvirus 1 Transcription and Productive Infection

Journal of Virology ◽

10.1128/jvi.00904-17 ◽

2017 ◽

Vol 91 (21) ◽

Cited By ~ 18

Author(s):

Fouad S. El-mayet ◽

Laximan Sawant ◽

Prasanth Thunuguntla ◽

Clinton Jones

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Glucocorticoid Receptor ◽

Sensory Neurons ◽

Viral Gene Expression ◽

Bovine Herpesvirus ◽

Productive Infection ◽

Viral Gene ◽

Bovine Herpesvirus 1 ◽

Herpesvirus 1

ABSTRACT Bovine herpesvirus 1 (BoHV-1), an important bovine pathogen, establishes lifelong latency in sensory neurons. Latently infected calves consistently reactivate from latency following a single intravenous injection of the synthetic corticosteroid dexamethasone. The immediate early transcription unit 1 (IEtu1) promoter, which drives bovine ICP0 (bICP0) and bICP4 expression, is stimulated by dexamethasone because it contains two glucocorticoid receptor (GR) response elements (GREs). Several Krüppel-like transcription factors (KLF), including KLF15, are induced during reactivation from latency, and they stimulate certain viral promoters and productive infection. In this study, we demonstrate that the GR and KLF15 were frequently expressed in the same trigeminal ganglion (TG) neuron during reactivation and cooperatively stimulated productive infection and IEtu1 GREs in mouse neuroblastoma cells (Neuro-2A). We further hypothesized that additional regions in the BoHV-1 genome are transactivated by the GR or stress-induced transcription factors. To test this hypothesis, BoHV-1 DNA fragments (less than 400 bp) containing potential GR and KLF binding sites were identified and examined for transcriptional activation by stress-induced transcription factors. Intergenic regions within the unique long 52 gene (UL52; a component of the DNA primase/helicase complex), bICP4, IEtu2, and the unique short region were stimulated by KLF15 and the GR. Chromatin immunoprecipitation studies revealed that the GR and KLF15 interacted with sequences within IEtu1 GREs and the UL52 fragment. Coimmunoprecipitation studies demonstrated that KLF15 and the GR were associated with each other in transfected cells. Since the GR stimulates KLF15 expression, we suggest that these two transcription factors form a feed-forward loop that stimulates viral gene expression and productive infection following stressful stimuli. IMPORTANCE Bovine herpesvirus 1 (BoHV-1) is an important viral pathogen that causes respiratory disease and suppresses immune responses in cattle; consequently, life-threatening bacterial pneumonia can occur. Following acute infection, BoHV-1 establishes lifelong latency in sensory neurons. Reactivation from latency is initiated by the synthetic corticosteroid dexamethasone. Dexamethasone stimulates lytic cycle viral gene expression in sensory neurons of calves latently infected with BoHV-1, culminating in virus shedding and transmission. Two stress-induced cellular transcription factors, Krüppel-like transcription factor 15 (KLF15) and the glucocorticoid receptor (GR), cooperate to stimulate productive infection and viral transcription. Additional studies demonstrated that KLF15 and the GR form a stable complex and that these stress-induced transcription factors bind to viral DNA sequences, which correlates with transcriptional activation. The ability of the GR and KLF15 to synergistically stimulate viral gene expression and productive infection may be critical for the ability of BoHV-1 to reactivate from latency following stressful stimuli.

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Temporal Dynamics of HCMV Gene Expression in Lytic and Latent Infections

10.1101/2021.07.26.453763 ◽

2021 ◽

Author(s):

Batsheva Rozman ◽

Yaarit Kitsberg ◽

Aharon Nachshon ◽

Michal Schwartz ◽

Noam Stern-Ginossar

Keyword(s):

Gene Expression ◽

Protein Synthesis ◽

Dna Replication ◽

Latent Infection ◽

Viral Gene Expression ◽

Productive Infection ◽

Viral Gene ◽

Viral Dna ◽

Viral Dna Replication ◽

Viral Genes

Primary infection with Human cytomegalovirus (HCMV) results in a persistent lifelong infection due to its ability to establish latent infection. During productive HCMV infection, viral genes are expressed in a coordinated cascade that is characteristic of all herpesviruses and traditionally relies on the dependencies of viral genes on protein synthesis and viral DNA replication. In contrast, the transcriptional landscape associated with HCMV latency is still disputed and poorly understood. Here, we examine viral transcriptomic dynamics during the establishment of both productive and latent HCMV infections. These temporal measurements reveal that viral gene expression dynamics along productive infection and their dependencies on protein synthesis and viral DNA replication, do not fully align. This illustrates that the regulation of herpesvirus genes does not represent a simple sequential transcriptional cascade and surprisingly many viral genes are regulated by multiple independent modules. Using our improved classification of viral gene expression kinetics in conjunction with transcriptome-wide measurements of the effects of a wide array of chromatin modifiers, we unbiasedly show that a defining characteristic of latent cells is the unique repression of immediate early (IE) genes. In particular, we demonstrate that IE1 (a central IE protein) expression is the principal barrier for achieving a full productive cycle. Altogether, our findings provide an unbiased and elaborate definition of HCMV gene expression in lytic and latent infection states.

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Motor Skills: Recruitment of Kinesins, Myosins and Dynein during Assembly and Egress of Alphaherpesviruses

Viruses ◽

10.3390/v13081622 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1622

Author(s):

Duncan W. Wilson

Keyword(s):

Gene Expression ◽

Nervous System ◽

Infected Cell ◽

Motor Skills ◽

Viral Gene Expression ◽

Productive Infection ◽

Viral Gene ◽

Challenging Problem ◽

Genome Packaging ◽

Initial Infection

The alphaherpesviruses are pathogens of the mammalian nervous system. Initial infection is commonly at mucosal epithelia, followed by spread to, and establishment of latency in, the peripheral nervous system. During productive infection, viral gene expression, replication of the dsDNA genome, capsid assembly and genome packaging take place in the infected cell nucleus, after which mature nucleocapsids emerge into the cytoplasm. Capsids must then travel to their site of envelopment at cytoplasmic organelles, and enveloped virions need to reach the cell surface for release and spread. Transport at each of these steps requires movement of alphaherpesvirus particles through a crowded and viscous cytoplasm, and for distances ranging from several microns in epithelial cells, to millimeters or even meters during egress from neurons. To solve this challenging problem alphaherpesviruses, and their assembly intermediates, exploit microtubule- and actin-dependent cellular motors. This review focuses upon the mechanisms used by alphaherpesviruses to recruit kinesin, myosin and dynein motors during assembly and egress.

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