scholarly journals Herpes Simplex Virus Type 1 Regulatory Protein ICP0 Does Not Protect Cyclins D1 and D3 from Degradation during Infection

2004 ◽  
Vol 78 (18) ◽  
pp. 9599-9604 ◽  
Author(s):  
Roger D. Everett
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Viral Infection ◽  
Herpes Simplex Virus Type ◽  
Regulatory Protein ◽  
Cell Type ◽  
Protein Icp0 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Previous reports have suggested that herpes simplex virus type 1 (HSV-1) immediate-early regulatory protein ICP0 stabilizes cyclins D1 and D3 during infection by inducing the degradation of cdc34, the E2-conjugating enzyme that is responsible for regulating the stability of these cyclins. Since ICP0 has complex effects on the progress of viral infection that vary greatly with cell type and viral dose, it can be difficult to distinguish between direct effects caused by ICP0 itself and indirect effects caused by the rate of the progression of infection in the absence of ICP0 at the chosen multiplicity of infection. This report describes the fates of cdc34 and cyclins D1 and D3 during HSV-1 infection under conditions that ensured that viral infection and gene expression were proceeding at equivalent rates in the presence and absence of ICP0. It was confirmed that both D-type cyclins were unstable during HSV-1 infection of a variety of cell types, but no effect on cdc34 was observed, even when high levels of ICP0 were expressed. Furthermore, there was no evidence that ICP0 protected either cyclin D1 or cyclin D3 from degradation. Reconstruction of the conditions of the experiments in the previous studies, using the stated cell type and multiplicities of infection, indicated that the original results could be explained by differences in the rate of progression of infection rather than by the presence or absence of ICP0. The data presented in this report are incompatible with the hypothesis that ICP0 induces the degradation of cdc34 and thereby stabilizes cyclins D1 and D3 during HSV-1 infection.

scholarly journals Depletion of CoREST Does Not Improve the Replication of ICP0 Null Mutant Herpes Simplex Virus Type 1

2010 ◽  
Vol 84 (7) ◽  
pp. 3695-3698 ◽  
Author(s):  
Roger D. Everett
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Regulatory Protein ◽  
Null Mutant ◽  
Protein Icp0 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT It has been proposed that the cellular corepressor protein CoREST is involved in repressing herpes simplex virus type 1 (HSV-1) infection in the absence of the viral regulatory protein ICP0. This proposal predicts that depletion of CoREST should improve the plaque-forming efficiency and replication of ICP0 null mutant virus. To test this hypothesis, human HepaRG cells that were highly depleted of CoREST were isolated using RNA interference technology. Depletion of CoREST had no effect on the replication of ICP0 null mutant HSV-1, demonstrating that CoREST does not play an influential role in regulating HSV-1 infection in this cell type.

scholarly journals Herpes Simplex Virus Type 1 Regulatory Protein ICP0 Aids Infection in Cells with a Preinduced Interferon Response but Does Not Impede Interferon-Induced Gene Induction

2009 ◽  
Vol 83 (10) ◽  
pp. 4978-4983 ◽  
Author(s):  
Roger D. Everett ◽  
Anne Orr
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Cultured Cells ◽  
Regulatory Protein ◽  
Multiplicity Of Infection ◽  
Protein Icp0 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Several independent lines of evidence indicate that interferon-mediated innate responses are involved in controlling herpes simplex virus type 1 (HSV-1) infection and that the viral immediate-early regulatory protein ICP0 augments HSV-1 replication in interferon-treated cells. However, this is a complex situation in which the experimental outcome is determined by the choice of multiplicity of infection and cell type and by whether cultured cells or animal models are used. It is now known that neither STAT1 nor interferon regulatory factor 3 (IRF-3) play essential roles in the replication defect of ICP0-null mutant HSV-1 in cultured cells. This study set out to investigate the specific role of ICP0 in HSV-1 resistance to the interferon defense. We have used a cell line in which ICP0 expression can be induced at levels similar to those during the early stages of a normal infection to determine whether ICP0 by itself can interfere with interferon or IRF-3-dependent signaling and whether ICP0 enables the virus to circumvent the effects of interferon-stimulated genes (ISGs). We found that the presence of ICP0 was unable to compromise ISG induction by either interferon or double-stranded RNA. On the other hand, ICP0 preexpression reduced but did not eliminate the inhibitory effects of ISGs on HSV-1 infection, with the extent of the relief being highly dependent on multiplicity of infection. The results are discussed in terms of the relationships between ICP0 and intrinsic and innate antiviral resistance mechanisms.

scholarly journals Analysis of the Functions of Herpes Simplex Virus Type 1 Regulatory Protein ICP0 That Are Critical for Lytic Infection and Derepression of Quiescent Viral Genomes

2009 ◽  
Vol 83 (10) ◽  
pp. 4963-4977 ◽  
Author(s):  
Roger D. Everett ◽  
Marie-Laure Parsy ◽  
Anne Orr
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Regulatory Protein ◽  
Lytic Infection ◽  
Viral Genomes ◽  
Protein Icp0 ◽  
Simplex Virus ◽  
Mutant Forms ◽  
Hsv 1

ABSTRACT Herpes simplex virus type 1 (HSV-1) immediate-early regulatory protein ICP0 is important for stimulating the initiation of the lytic cycle and efficient reactivation of latent or quiescent infection. Extensive investigation has suggested several potential functions for ICP0, including interference in the interferon response, disruption of functions connected with PML nuclear bodies (ND10), and inhibition of cellular histone deacetylase (HDAC) activity through an interaction with the HDAC-1 binding partner CoREST. Analysis of the significance of these potential functions and whether they are direct or indirect effects of ICP0 is complicated because HSV-1 mutants expressing mutant forms of ICP0 infect cells with widely differing efficiencies. On the other hand, transfection approaches for ICP0 expression do not allow studies of whole cell populations because of their limited efficiency. To overcome these problems, we have established a cell line in which ICP0 expression can be induced at levels pertaining during the early stages of HSV-1 infection in virtually all cells in the culture. Such cells enable 100% complementation of ICP0-null mutant HSV-1. Using cells expressing the wild type and a variety of mutant forms of ICP0, we have used this system to analyze the role of defined domains of the protein in stimulating lytic infection and derepression from quiescence. Activity in these core functions correlated well the ability of ICP0 to disrupt ND10 and inhibit the recruitment of ND10 proteins to sites closely associated with viral genomes at the onset of infection, whereas the CoREST binding region was neither sufficient nor necessary for ICP0 function in lytic and reactivating infections.

scholarly journals Neurodegeneration in human brain organoids infected with herpes simplex virus type 1

2021 ◽  
Author(s):  
Agnieszka Rybak-Wolf ◽  
Emanuel Wyler ◽  
Ivano Legnini ◽  
Anna Loewa ◽  
Petar Glažar ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Human Brain ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Cell Type ◽  
Cell Type Specific ◽  
Simplex Virus ◽  
Hsv 1

AbstractHerpes simplex virus type 1 (HSV-1) infection of the nervous system may lead to brain damage, including neurodegeneration. However, lack of suitable experimental models hinders understanding molecular mechanisms and cell-type-specific responses triggered by HSV-1. Here, we infected human brain organoids with HSV-1. Known features of HSV-1 infection such as alteration of neuronal electrophysiology and induction of antisense transcription were confirmed. Full-length mRNA-sequencing revealed aberrant 3’ end formation and poly(A)-tail lengthening. Single-cell RNA-seq and spatial transcriptomics uncovered changes in the cellular composition of the infected organoids caused by viral replication and dysregulation of molecular pathways in cell-type specific manner. Furthermore, hallmarks of early neurodegeneration were observed, namely extracellular matrix disruption, STMN2 and TARDBP/TDP43 downregulation, and upregulation of the AD-related non-coding RNA BC200/BCYRN1. These hallmarks were weaker/absent when infecting with a mutant HSV-1 control. Together, our data indicate that brain organoids serve as a powerful model to study mechanisms of HSV-1-driven neurodegeneration.

scholarly journals Herpes simplex virus type 1 infection and glucocorticoid treatment regulate viral yield, glucocorticoid receptor and NF-kappaB levels

2002 ◽  
Vol 175 (1) ◽  
pp. 165-176 ◽  
Author(s):  
AC Erlandsson ◽  
LG Bladh ◽  
P Stierna ◽  
T Yucel-Lindberg ◽  
O Hammarsten ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Viral Infection ◽  
Herpes Simplex Virus Type ◽  
Glucocorticoid Treatment ◽  
Viral Yield ◽  
Nf Kappab ◽  
Simplex Virus ◽  
Hsv 1

The interplay between the endocrine and immune systems has come into focus in recent years with the insight that endocrine parameters may affect susceptibility to both auto-immune and infectious diseases. Our interest in immunoendocrine regulation led us to investigate the effects of glucocorticoids on Herpes simplex virus type 1 (HSV-1) infections. Glucocorticoids used to treat inflammatory conditions are not yet recommended for HSV-1 therapy, since they have been reported to prolong viral shedding both in vivo and in vitro. Here we report that glucocorticoids did not alter the viral yield in human gingival fibroblast (HGF) cell culture when glucocorticoid treatment and viral infection occured simultaneously, but the viral yield increased when cells were treated with the glucocorticoid dexamethasone (dex) prior to viral infection. We found that viral infection in our primary cell system increased NF-kappaB levels and DNA binding. In addition, the amount of glucocorticoid receptor (GR) increased following viral infection, and HSV-1 infection as such could induce glucocorticoid-driven transcription of a reporter gene in human embryo kidney (HEK) 293 cells stably transfected with GR. Dex treatment did not affect HSV-1-induced binding of p65 to an NF-kappaB element in an electrophoretic mobility shift assay, and acyclovir was still efficient as an anti-viral drug in the presence of dex. Further studies of the observed effects of HSV-1 infection and glucocorticoid treatment on GR and NF-kappaB regulation could give insights into the immunoendocrine mechanisms important for defence and therapy against viral infections.

scholarly journals Interactions of Herpes Simplex Virus Type 1 with ND10 and Recruitment of PML to Replication Compartments

2001 ◽  
Vol 75 (5) ◽  
pp. 2353-2367 ◽  
Author(s):  
Jennifer Burkham ◽  
Donald M. Coen ◽  
Charles B. C. Hwang ◽  
Sandra K. Weller
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Viral Infection ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Stage Iii ◽  
Nuclear Domains ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Many of the events required for productive herpes simplex virus type 1 (HSV-1) infection occur within globular nuclear domains called replication compartments, whose formation appears to depend on interactions with cellular nuclear domains 10 (ND10). We have previously demonstrated that the formation of HSV-1 replication compartments involves progression through several stages, including the disruption of intact ND10 (stage I to stage II) and the formation of PML-associated prereplicative sites (stage III) and replication compartments (stage IV) (J. Burkham, D. M. Coen, and S. K. Weller, J. Virol. 72:10100–10107, 1998). In this paper, we show that some, but not all, PML isoforms are recruited to stage III foci and replication compartments. Genetic experiments showed that the recruitment of PML isoforms to stage III prereplicative sites and replication compartments requires the localization of the HSV-1 polymerase protein (UL30) to these foci but does not require polymerase catalytic activity. We also examined the stages of viral infection under conditions affecting ND10 integrity. Treatment with factors that increase the stability of ND10, arsenic trioxide and the proteasome inhibitor MG132, inhibited viral disruption of ND10, formation of replication compartments, and production of progeny virus. These results strengthen the previously described correlation between ND10 disruption and productive viral infection.

scholarly journals Reciprocal Activities between Herpes Simplex Virus Type 1 Regulatory Protein ICP0, a Ubiquitin E3 Ligase, and Ubiquitin-Specific Protease USP7

2005 ◽  
Vol 79 (19) ◽  
pp. 12342-12354 ◽  
Author(s):  
Chris Boutell ◽  
Mary Canning ◽  
Anne Orr ◽  
Roger D. Everett
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Regulatory Protein ◽  
Ring Finger ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Protein Icp0 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Herpes simplex virus type 1 (HSV-1) regulatory protein ICP0 stimulates lytic infection and the reactivation of quiescent viral genomes. These roles of ICP0 require its RING finger E3 ubiquitin ligase domain, which induces the degradation of several cellular proteins, including components of promyelocytic leukemia nuclear bodies and centromeres. ICP0 also interacts very strongly with the cellular ubiquitin-specific protease USP7 (also known as HAUSP). We have shown previously that ICP0 induces its own ubiquitination and degradation in a RING finger-dependent manner, and that its interaction with USP7 regulates this process. In the course of these studies we found and report here that ICP0 also targets USP7 for ubiquitination and proteasome-dependent degradation. The reciprocal activities of the two proteins reveal an intriguing situation that poses the question of the balance of the two processes during productive HSV-1 infection. Based on a thorough analysis of the properties of an HSV-1 mutant virus that expresses forms of ICP0 that are unable to bind to USP7, we conclude that USP7-mediated stabilization of ICP0 is dominant over ICP0-induced degradation of USP7 during productive HSV-1 infection. We propose that the biological significance of the ICP0-USP7 interaction may be most pronounced in natural infection situations, in which limited amounts of ICP0 are expressed.

scholarly journals Analysis of the Phosphorylation Sites of Herpes Simplex Virus Type 1 Regulatory Protein ICP27

1999 ◽  
Vol 73 (4) ◽  
pp. 3246-3257 ◽  
Author(s):  
Yan Zhi ◽  
Rozanne M. Sandri-Goldin
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Viral Infection ◽  
Herpes Simplex Virus Type ◽  
Regulatory Protein ◽  
Phosphorylation Sites ◽  
Simplex Virus ◽  
Phosphate Groups

ABSTRACT The herpes simplex virus type 1 (HSV-1) regulatory protein ICP27 is a 63-kDa phosphoprotein required for viral replication. ICP27 has been shown to contain both stable phosphate groups and phosphate groups that cycle on and off during infection (K. W. Wilcox, A. Kohn, E. Sklyanskaya, and B. Roizman, J. Virol. 33:167–182, 1980). Despite extensive genetic analysis of the ICP27 gene, there is no information available about the sites of the ICP27 molecule that are phosphorylated during viral infection. In this study, we mapped several of the phosphorylation sites of ICP27 following in vivo radiolabeling. Phosphoamino acid analysis showed that serine is the only amino acid that is phosphorylated during infection. Two-dimensional phosphopeptide mapping showed a complex tryptic phosphopeptide pattern with at least four major peptides and several minor peptides. In addition, ICP27 purified from transfected cells yielded a similar phosphopeptide pattern, suggesting that cellular kinases phosphorylate ICP27 during viral infection. In vitro labeling showed that protein kinase A (PKA), PKC, and casein kinase II (CKII) were able to differentially phosphorylate ICP27, resulting in distinct phosphopeptide patterns. The major phosphorylation sites of ICP27 appeared to cluster in the N-terminal portion of the protein, such that a frameshift mutant that encodes amino acids 1 to 163 yielded a phosphopeptide pattern very similar to that seen with the wild-type protein. Further, using small deletion and point mutations in kinase consensus sites, we have elucidated individual serine residues that are phosphorylated in vivo. Specifically, the serine at residue 114 was highly phosphorylated by PKA and the serine residues at positions 16 and 18 serve as targets for CKII phosphorylation in vivo. These kinase consensus site mutants were still capable of complementing the growth of an ICP27-null mutant virus. Interestingly, phosphorylation of the serine at residue 114, which lies within the major nuclear localization signal, appeared to modulate the efficiency of nuclear import of ICP27.

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