scholarly journals The Human Adenovirus Type 5 E4orf6/E1B55K E3 Ubiquitin Ligase Complex Can Mimic E1A Effects on E2F

mSphere ◽  
2015 ◽  
Vol 1 (1) ◽  
Author(s):  
Frédéric Dallaire ◽  
Sabrina Schreiner ◽  
G. Eric Blair ◽  
Thomas Dobner ◽  
Philip E. Branton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Dna Synthesis ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Viral Gene Expression ◽  
Adenovirus Vector ◽  
Human Adenovirus ◽  
Viral Gene ◽  
E2f Transcription Factors

ABSTRACT During the course of work on the adenovirus E3 ubiquitin ligase formed by the viral E4orf6 and E1B55K proteins, we found, very surprisingly, that expression of these species was sufficient to permit low levels of replication of an adenovirus vector lacking E1A, the central regulator of infection. E1A products uncouple E2F transcription factors from Rb repression complexes, thus stimulating viral gene expression and cell and viral DNA synthesis. We found that the E4orf6/E1B55K ligase mimics these functions. This finding is of significance because it represents an entirely new function for the ligase in regulating adenovirus replication. The human adenovirus E4orf6/E1B55K E3 ubiquitin ligase is well known to promote viral replication by degrading an increasing number of cellular proteins that inhibit the efficient production of viral progeny. We report here a new function of the adenovirus 5 (Ad5) viral ligase complex that, although at lower levels, mimics effects of E1A products on E2F transcription factors. When expressed in the absence of E1A, the E4orf6 protein in complex with E1B55K binds E2F, disrupts E2F/retinoblastoma protein (Rb) complexes, and induces hyperphosphorylation of Rb, leading to induction of viral and cellular DNA synthesis as well as stimulation of early and late viral gene expression and production of viral progeny of E1/E3-defective adenovirus vectors. These new and previously undescribed functions of the E4orf6/E1B55K E3 ubiquitin ligase could play an important role in promoting the replication of wild-type viruses. IMPORTANCE During the course of work on the adenovirus E3 ubiquitin ligase formed by the viral E4orf6 and E1B55K proteins, we found, very surprisingly, that expression of these species was sufficient to permit low levels of replication of an adenovirus vector lacking E1A, the central regulator of infection. E1A products uncouple E2F transcription factors from Rb repression complexes, thus stimulating viral gene expression and cell and viral DNA synthesis. We found that the E4orf6/E1B55K ligase mimics these functions. This finding is of significance because it represents an entirely new function for the ligase in regulating adenovirus replication.

scholarly journals The Human Adenovirus Type 5 E4orf6/E1B55K E3 Ubiquitin Ligase Complex Enhances E1A Functional Activity

mSphere ◽  
2015 ◽  
Vol 1 (1) ◽  
Author(s):  
Frédéric Dallaire ◽  
Sabrina Schreiner ◽  
G. Eric Blair ◽  
Thomas Dobner ◽  
Philip E. Branton ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Viral Gene Expression ◽  
Human Adenovirus ◽  
Viral Gene ◽  
Ubiquitin Ligase Complex ◽  
Cellular Dna ◽  
Adenovirus Replication ◽  
Do So

ABSTRACT Following our demonstration that adenovirus E3 ubiquitin ligase formed by the viral E4orf6 and E1B55K proteins is able to mimic the activation of E2F by E1A, we conducted a series of studies to determine if this complex might also promote the ability of E1A to do so. We found that the complex both significantly stabilizes E1A proteins and also enhances their ability to activate E2F. This finding is of significance because it represents an entirely new function for the ligase in regulating adenovirus replication by enhancing the action of E1A products. Human adenovirus (Ad) E1A proteins have long been known as the central regulators of virus infection as well as the major source of adenovirus oncogenic potential. Not only do they activate expression of other early viral genes, they make viral replication possible in terminally differentiated cells, at least in part, by binding to the retinoblastoma (Rb) tumor suppressor family of proteins to activate E2F transcription factors and thus viral and cellular DNA synthesis. We demonstrate in an accompanying article (F. Dallaire et al., mSphere 1:00014-15, 2016) that the human adenovirus E3 ubiquitin ligase complex formed by the E4orf6 and E1B55K proteins is able to mimic E1A activation of E2F transactivation factors. Acting alone in the absence of E1A, the Ad5 E4orf6 protein in complex with E1B55K was shown to bind E2F, disrupt E2F/Rb complexes, and induce hyperphosphorylation of Rb, leading to induction of viral and cellular DNA synthesis, as well as stimulation of early and late viral gene expression and production of viral progeny. While these activities were significantly lower than those exhibited by E1A, we report here that this ligase complex appeared to enhance E1A activity in two ways. First, the E4orf6/E1B55K complex was shown to stabilize E1A proteins, leading to higher levels in infected cells. Second, the complex was demonstrated to enhance the activation of E2F by E1A products. These findings indicated a new role of the E4orf6/E1B55K ligase complex in promoting adenovirus replication. IMPORTANCE Following our demonstration that adenovirus E3 ubiquitin ligase formed by the viral E4orf6 and E1B55K proteins is able to mimic the activation of E2F by E1A, we conducted a series of studies to determine if this complex might also promote the ability of E1A to do so. We found that the complex both significantly stabilizes E1A proteins and also enhances their ability to activate E2F. This finding is of significance because it represents an entirely new function for the ligase in regulating adenovirus replication by enhancing the action of E1A products.

CMV DNA synthesis and late viral gene expression

2010 ◽  
pp. 295-310 ◽  
Author(s):  
David G. Anders ◽  
Julie A. Kerry ◽  
Gregory S. Pari
Keyword(s):  
Gene Expression ◽  
Dna Synthesis ◽  
Viral Gene Expression ◽  
Viral Gene

scholarly journals The EHV-1 UL4 protein that tempers viral gene expression interacts with cellular transcription factors

Virology ◽  
2014 ◽  
Vol 449 ◽  
pp. 25-34 ◽  
Author(s):  
Yunfei Zhang ◽  
Robert A. Charvat ◽  
Seong K. Kim ◽  
Dennis J. O’Callaghan
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Cellular Transcription

scholarly journals Epigenomic characterization of latent HIV infection identifies latency regulating transcription factors

2021 ◽  
Vol 17 (2) ◽  
pp. e1009346
Author(s):  
Stuart R. Jefferys ◽  
Samuel D. Burgos ◽  
Jackson J. Peterson ◽  
Sara R. Selitsky ◽  
Anne-Marie W. Turner ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Transcription Factors ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Hiv Latency ◽  
Latently Infected ◽  
Infected Cells

Transcriptional silencing of HIV in CD4 T cells generates a reservoir of latently infected cells that can reseed infection after interruption of therapy. As such, these cells represent the principal barrier to curing HIV infection, but little is known about their characteristics. To further our understanding of the molecular mechanisms of latency, we characterized a primary cell model of HIV latency in which infected cells adopt heterogeneous transcriptional fates. In this model, we observed that latency is a stable, heritable state that is transmitted through cell division. Using Assay of Transposon-Accessible Chromatin sequencing (ATACseq) we found that latently infected cells exhibit greatly reduced proviral accessibility, indicating the presence of chromatin-based structural barriers to viral gene expression. By quantifying the activity of host cell transcription factors, we observe elevated activity of Forkhead and Kruppel-like factor transcription factors (TFs), and reduced activity of AP-1, RUNX and GATA TFs in latently infected cells. Interestingly, latency reversing agents with different mechanisms of action caused distinct patterns of chromatin reopening across the provirus. We observe that binding sites for the chromatin insulator CTCF are highly enriched in the differentially open chromatin of infected CD4 T cells. Furthermore, depletion of CTCF inhibited HIV latency, identifying this factor as playing a key role in the initiation or enforcement of latency. These data indicate that HIV latency develops preferentially in cells with a distinct pattern of TF activity that promotes a closed proviral structure and inhibits viral gene expression. Furthermore, these findings identify CTCF as a novel regulator of HIV latency.

scholarly journals Extracellular Signal-Regulated Kinase Activity Is Sustained Early during Human Cytomegalovirus Infection

1998 ◽  
Vol 72 (11) ◽  
pp. 9173-9180 ◽  
Author(s):  
Steven M. Rodems ◽  
Deborah H. Spector
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Transcription Factors ◽  
Protein Kinase ◽  
Hcmv Infection ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Extracellular Signal ◽  
Erk Activity ◽  
Cellular Transcription

ABSTRACT Expression of many early viral genes during human cytomegalovirus (HCMV) infection is dependent on cellular transcription factors. Several immediate-early and early viral promoters contain DNA binding sites for cellular factors such as CREB, AP-1, serum response factor, and Elk-1, and these transcription factors can be activated by phosphorylation via the cellular mitogen-activated protein kinase (MAPK) signal transduction cascade. To determine if the extracellular signal-regulated MAPKs, ERK1 and ERK2, play a role in transcription factor activation during infection, we tested for ERK activity during viral infection. We found that HCMV infection resulted in the maintenance of previously activated ERK1 and ERK2 by a mechanism which appears to involve the inhibition of a cellular phosphatase activity. ERK phosphorylation and activity were sustained for at least 8 h after infection, whereas in mock-infected cells, ERK activity steadily declined by 1 h postinfection. The activity of at least one cellular substrate of the ERKs, the protein kinase RSK1, was also maintained during this period. UV inactivation experiments suggested that viral gene expression was required for sustained ERK activity. In turn, activation of the ERKs appeared to be important for viral gene expression, as evidenced by the observed decrease in the transcriptional activity of the HCMV UL112-113 promoter during infection in the presence of the MEK inhibitor PD98059. These data suggest that HCMV utilizes cellular signal transduction pathways to activate viral or cellular transcription factors involved in the control of early viral gene expression and DNA replication.

scholarly journals ERK1/2 and MEK1/2 Induced by Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Early during Infection of Target Cells Are Essential for Expression of Viral Genes and for Establishment of Infection

2005 ◽  
Vol 79 (16) ◽  
pp. 10308-10329 ◽  
Author(s):  
Neelam Sharma-Walia ◽  
Harinivas H. Krishnan ◽  
Pramod P. Naranatt ◽  
Ling Zeng ◽  
Marilyn S. Smith ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Growth Factor ◽  
De Novo ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Target Cells ◽  
Viral Dna ◽  
Erk Inhibition ◽  
Host Genes

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) in vitro target cell infection is characterized by the expression of the latency-associated genes ORF 73 (LANA-1), ORF 72, and K13 and by the transient expression of a very limited number of lytic genes such as lytic cycle switch gene ORF 50 (RTA) and the immediate early (IE) lytic K5, K8, and v-IRF2 genes. During the early stages of infection, several overlapping multistep complex events precede the initiation of viral gene expression. KSHV envelope glycoprotein gB induces the FAK-Src-PI3K-RhoGTPase (where FAK is focal adhesion kinase) signaling pathway. As early as 5 min postinfection (p.i.), KSHV induced the extracellular signal-regulated kinase 1 and 2 (ERK1/2) via the PI3K-PKCζ-MEK pathway. In addition, KSHV modulated the transcription of several host genes of primary human dermal microvascular endothelial cells (HMVEC-d) and fibroblast (HFF) cells by 2 h and 4 h p.i. Neutralization of virus entry and infection by PI-3K and other cellular tyrosine kinase inhibitors suggested a critical role for signaling molecules in KSHV infection of target cells. Here we investigated the induction of ERK1/2 by KSHV and KSHV envelope glycoproteins gB and gpK8.1A and the role of induced ERK in viral and host gene expression. Early during infection, significant ERK1/2 induction was observed even with low multiplicity of infection of live and UV-inactivated KSHV in serum-starved cells as well as in the presence of serum. Entry of UV-inactivated virus and the absence of viral gene expression suggested that ERK1/2 induction is mediated by the initial signal cascade induced by KSHV binding and entry. Purified soluble gpK8.1A induced the MEK1/2 dependent ERK1/2 but not ERK5 and p38 mitogen-activated protein kinase (MAPK) in HMVEC-d and HFF. Moderate ERK induction with soluble gB was seen only in HMVEC-d. Preincubation of gpK8.1A with heparin or anti-gpK8.1A antibodies inhibited the ERK induction. U0126, a selective inhibitor for MEK/ERK blocked the gpK8.1A- and KSHV-induced ERK activation. ERK1/2 inhibition did not block viral DNA internalization and had no significant effect on nuclear delivery of KSHV DNA during de novo infection. Analyses of viral gene expression by quantitative real-time reverse transciptase PCR revealed that pretreatment of cells with U0126 for 1 h and during the 2-h infection with KSHV significantly inhibited the expression of ORF 73, ORF 50 (RTA), and the IE-K8 and v-IRF2 genes. However, the expression of lytic IE-K5 gene was not affected significantly. Expression of ORF 73 in BCBL-1 cells was also significantly inhibited by preincubation with U0126. Inhibition of ERK1/2 also inhibited the transcription of some of the vital host genes such as DUSP5 (dual specificity phosphatase 5), ICAM-1 (intercellular adhesion molecule 1), heparin binding epidermal growth factor, and vascular endothelial growth factor that were up-regulated early during KSHV infection. Several MAPK-regulated host transcription factors such as c-Jun, STAT1α, MEF2, c-Myc, ATF-2 and c-Fos were induced early during infection, and ERK inhibition significantly blocked the c-Fos, c-Jun, c-Myc, and STAT1α activation in the infected cells. AP1 transcription factors binding to the RTA promoter in electrophoretic mobility shift assays were readily detected in the infected cell nuclear extracts which were significantly reduced by ERK inhibition. Together, these results suggest that very early during de novo infection, KSHV induces the ERK1/2 to modulate the initiation of viral gene expression and host cell genes, which further supports our hypothesis that beside the conduit for viral DNA delivery into the cytoplasm, KSHV interactions with host cell receptor(s) create an appropriate intracellular environment facilitating infection.

scholarly journals pVHL regulates protein stability of TCF/LEF transcription factor family via ubiquitin-independent proteasomal degradation

2021 ◽  
Author(s):  
Caixia Wang ◽  
Xiaozhi Rong ◽  
Haifeng Zhang ◽  
Bo Wang ◽  
Yan Bai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Protein Stability ◽  
Ubiquitin Ligase ◽  
Target Gene ◽  
E3 Ubiquitin Ligase ◽  
Proteasomal Degradation ◽  
26S Proteasome ◽  
Cell Fate Decisions ◽  
Target Gene Expression

The Wnt/β-catenin signaling pathway plays key roles in development and adult tissue homeostasis by controlling cell proliferation and cell fate decisions. In this pathway, transcription factors TCF/LEFs are the key components to repress target gene expression by recruiting co-repressors or to activate target gene expression by recruiting β-catenin when the Wnt signals are absent or present, respectively. While progress has been made in our understanding of Wnt signaling regulation, the underlying mechanism that regulates the protein stability of the TCF/LEF family is far less clear. Here, we show that von Hippel-Lindau protein (pVHL), which is the substrate recognition component in an E3 ubiquitin ligase complex, controls TCF/LEF protein stability. Unexpectedly, pVHL directly binds to TCF/LEFs and promotes their proteasomal degradation independent of E3 ubiquitin ligase activity. Knockout of vhl in zebrafish embryos leads to a reduction of dorsal habenular neurons and this effect is upstream of dorsal habenular neurons phenotype in tcf7l2-null mutants. Our study uncovers a previously unknown mechanism for the protein stability regulation of the TCF/LEF transcription factors and demonstrates that pVHL contains a 26S proteasome binding domain that drives ubiquitin-independent proteasomal degradation. These findings provide new insights into the ubiquitin-independent actions of pVHL and uncover novel mechanistical regulation of Wnt/β-catenin signaling.

scholarly journals E1B-55K-Mediated Regulation of RNF4 SUMO-Targeted Ubiquitin Ligase Promotes Human Adenovirus Gene Expression

2018 ◽  
Vol 92 (13) ◽  
Author(s):  
Sarah Müncheberg ◽  
Ron T. Hay ◽  
Wing H. Ip ◽  
Tina Meyer ◽  
Christina Weiß ◽  
...  
Keyword(s):  
Gene Expression ◽  
Infected Cell ◽  
Viral Replication ◽  
Ubiquitin Ligase ◽  
Posttranslational Modification ◽  
E3 Ubiquitin Ligase ◽  
Human Adenovirus ◽  
Productive Infection ◽  
Dependent Manner ◽  
Ubiquitin Ligase Complex

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.

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

2017 ◽  
Vol 91 (21) ◽  
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.

scholarly journals The Late Promoter of the Human Cytomegalovirus Viral DNA Polymerase Processivity Factor Has an Impact on Delayed Early and Late Viral Gene Products but Not on Viral DNA Synthesis

2007 ◽  
Vol 81 (12) ◽  
pp. 6197-6206 ◽  
Author(s):  
Hiroki Isomura ◽  
Mark F. Stinski ◽  
Ayumi Kudoh ◽  
Sanae Nakayama ◽  
Satoko Iwahori ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Synthesis ◽  
Dna Polymerase ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Wild Type ◽  
Viral Dna ◽  
Recombinant Viruses ◽  
Tata Element ◽  
Processivity Factor

ABSTRACT Transcription of the DNA polymerase processivity factor gene (UL44) of human cytomegalovirus initiates at three distinct start sites, which are differentially regulated during productive infection. Two of these start sites, the distal and proximal sites, are active at early times, and the middle start site is active at only late times after infection (F. Leach and E. S. Mocarski, J. Virol. 63:1783-1791, 1989). Compared to the wild type, UL44 gene expression was lower for recombinant viruses with the distal or the middle TATA element mutated. The transcripts initiating from the distal or middle start site facilitated late viral gene expression. The level of viral DNA synthesis was affected by mutation of the distal TATA element. In contrast, mutation of the middle TATA element did not affect the level of viral DNA synthesis, but it did affect significantly the level of late viral gene expression. Recombinant viruses with the distal or middle TATA element mutated grew more slowly than the wild type at both low and high multiplicities of infection. Reduced expression of the UL44 gene from the late middle viral promoter correlated with decreased late viral protein expression and decreased viral growth.

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