scholarly journals ICP0 Gene Expression Is a Herpes Simplex Virus Type 1 Apoptotic Trigger

2006 ◽  
Vol 80 (14) ◽  
pp. 6810-6821 ◽  
Author(s):  
Christine M. Sanfilippo ◽  
John A. Blaho
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Apoptosis Induction ◽  
Infected Cells ◽  
Simplex Virus

ABSTRACT Apoptosis is a highly regulated programmed cell death process which is activated during normal development and by various stimuli, such as viral infection, which disturb cellular metabolism and physiology. That herpes simplex virus type 1 (HSV-1) induces apoptosis but then prevents its killing of infected cells is well-established. However, little is known about the viral factor/event which triggers the apoptotic process. We previously reported that infections with either (i) a temperature-sensitive virus at its nonpermissive temperature which does not inject viral DNA into nuclei or (ii) various UV-inactivated wild-type viruses do not result in the induction of apoptosis (C. M. Sanfilippo, F. N. W. Chirimuuta, and J. A. Blaho, J. Virol. 78:224-239, 2004). This indicates that virus receptor binding/attachment to cells, membrane fusion, virion disassembly/tegument dispersal, virion RNAs, and capsid translocation to nuclei are not responsible for induction and implicates viral immediate-early (IE) gene expression in the process. Here, we systematically evaluated the contribution of each IE gene to the stimulation of apoptosis. Using a series of viruses individually deleted for α27, α4, and α22, we determined that these genes are not required for apoptosis induction but rather that their products play roles in its prevention, likely through regulatory effects. Sole expression of α0 acted as an “apoptoxin” that was necessary and sufficient to trigger the cell death cascade. Importantly, results using a recombinant virus which contains a stop codon in α0 showed that it was not the ICP0 protein which acted as the apoptotic inducer. Based on these findings, we propose that α0 gene expression acts as an initial inducer of apoptosis during HSV-1 infection. This represents the first description of apoptosis induction in infected cells triggered as a result of expression of a single viral gene. Expression of apoptotic viral genes is a unique mechanism through which human pathogens may modulate interactions with their host cells.

scholarly journals Replication of ICP0-Null Mutant Herpes Simplex Virus Type 1 Is Restricted by both PML and Sp100

2007 ◽  
Vol 82 (6) ◽  
pp. 2661-2672 ◽  
Author(s):  
Roger D. Everett ◽  
Carlos Parada ◽  
Philippe Gripon ◽  
Hüseyin Sirma ◽  
Anne Orr
Keyword(s):  
Gene Expression ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Human Fibroblasts ◽  
Null Mutant ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Herpes simplex virus type 1 (HSV-1) mutants that fail to express the viral immediate-early protein ICP0 have a pronounced defect in viral gene expression and plaque formation in limited-passage human fibroblasts. ICP0 is a RING finger E3 ubiquitin ligase that induces the degradation of several cellular proteins. PML, the organizer of cellular nuclear substructures known as PML nuclear bodies or ND10, is one of the most notable proteins that is targeted by ICP0. Depletion of PML from human fibroblasts increases ICP0-null mutant HSV-1 gene expression, but not to wild-type levels. In this study, we report that depletion of Sp100, another major ND10 protein, results in a similar increase in ICP0-null mutant gene expression and that simultaneous depletion of both proteins complements the mutant virus to a greater degree. Although chromatin assembly and modification undoubtedly play major roles in the regulation of HSV-1 infection, we found that inhibition of histone deacetylase activity with trichostatin A was unable to complement the defect of ICP0-null mutant HSV-1 in either normal or PML-depleted human fibroblasts. These data lend further weight to the hypothesis that ND10 play an important role in the regulation of HSV-1 gene expression.

The protein ICP0 of herpes simplex virus type 1 is targeted to nucleoli of infected cells

2005 ◽  
Vol 150 (11) ◽  
pp. 2387-2395 ◽  
Author(s):  
E. Morency ◽  
Y. Couté ◽  
J. Thomas ◽  
P. Texier ◽  
P. Lomonte
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Infected Cells ◽  
Protein Icp0 ◽  
Simplex Virus

scholarly journals Specific Histone Tail Modification and Not DNA Methylation Is a Determinant of Herpes Simplex Virus Type 1 Latent Gene Expression

2004 ◽  
Vol 78 (3) ◽  
pp. 1139-1149 ◽  
Author(s):  
Nicole J. Kubat ◽  
Robert K. Tran ◽  
Peterjon McAnany ◽  
David C. Bloom
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Epigenetic Mechanism ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT During herpes simplex virus type 1 (HSV-1) latency, gene expression is tightly repressed except for the latency-associated transcript (LAT). The mechanistic basis for this repression is unknown, but its global nature suggests regulation by an epigenetic mechanism such as DNA methylation. Previous work demonstrated that latent HSV-1 genomes are not extensively methylated, but these studies lacked the resolution to examine methylation of individual CpGs that could repress transcription from individual promoters during latency. To address this point, we employed established models to predict genomic regions with the highest probability of being methylated and, using bisulfite sequencing, analyzed the methylation profiles of these regions. We found no significant methylation of latent DNA isolated from mouse dorsal root ganglia in any of the regions examined, including the ICP4 and LAT promoters. This analysis indicates that methylation is unlikely to play a major role in regulating HSV-1 latent gene expression. Subsequently we focused on differential histone modification as another epigenetic mechanism that could regulate latent transcription. Chromatin immunoprecipitation analysis of the latent HSV-1 DNA repeat regions demonstrated that a portion of the LAT region is associated with histone H3 acetylated at lysines 9 and 14, consistent with a euchromatic and nonrepressed structure. In contrast, the chromatin associated with the HSV-1 DNA polymerase gene located in the unique long segment was not enriched in H3 acetylated at lysines 9 and 14, suggesting a transcriptionally inactive structure. These data suggest that histone composition may be a major regulatory determinant of HSV latency.

scholarly journals Activation of cellular interferon-responsive genes after infection of human cells with herpes simplex virus type 1

2000 ◽  
Vol 81 (9) ◽  
pp. 2215-2218 ◽  
Author(s):  
Mary Jane Nicholl ◽  
Laurence H. Robinson ◽  
Chris M. Preston
Keyword(s):  
Gene Expression ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Human Fibroblasts ◽  
Interferon Α ◽  
Simplex Virus ◽  
Hsv 1

Previous studies have shown that infection of human fibroblasts with human cytomegalovirus (HCMV) results in activation of cellular interferon-responsive gene expression. We demonstrate here that infection of human fibroblasts with herpes simplex virus type 1 (HSV-1) in the absence of de novo protein synthesis also induces the expression of interferon-responsive genes. Five genes tested (encoding ISG54, IFI56, ISG15, 9-27 and MxA) were activated by infection with HSV-1, although the degree of response varied between the individual genes. HSV-1 was a less efficient inducer than HCMV. The effect was a consequence of binding of the virus particle to the cell surface or of the presence of virion components within the infected cell. Induction was mediated by a pathway other than the mechanism through which interferon-α mediates its effects on cellular gene expression.

scholarly journals Expression of the herpes simplex virus type 1 latency-associated transcripts does not influence latency establishment of virus mutants deficient for neuronal replication

2013 ◽  
Vol 94 (11) ◽  
pp. 2489-2494 ◽  
Author(s):  
M. P. Nicoll ◽  
S. Efstathiou
Keyword(s):  
Gene Expression ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Viral Gene ◽  
Peripheral Tissues ◽  
Lytic Gene ◽  
Simplex Virus

Herpes simplex virus type 1 establishes latency within neurons of the trigeminal ganglion. During latency, viral gene expression is largely restricted to the latency-associated transcripts (LATs), which, whilst not essential for any aspect of latency, function to suppress lytic gene expression and enhance the survival of virus-infected neurons. The latent cell population comprises primary-order neurons infected directly from peripheral tissues and cells infected following further virus spread within the ganglion. In order to assess the role of LAT expression on latency establishment within first-order neurons, we infected ROSA26R reporter mice with Cre recombinase-expressing recombinant viruses harbouring deletion of the thymidine kinase lytic gene and/or the core LAT promoter. We found that LAT expression did not impact on latency establishment in viruses unable to replicate in neurons, and under these conditions, it was not required for the survival of neurons between 3 and 31 days post-infection.

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