scholarly journals A Protein Encoded by the Herpes Simplex Virus (HSV) Type 1 2-Kilobase Latency-Associated Transcript Is Phosphorylated, Localized to the Nucleus, and Overcomes the Repression of Expression from Exogenous Promoters When Inserted into the Quiescent HSV Genome

2002 ◽  
Vol 76 (8) ◽  
pp. 4056-4067 ◽  
Author(s):  
S. K. Thomas ◽  
C. E. Lilley ◽  
D. S. Latchman ◽  
R. S. Coffin
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cell Types ◽  
Current Evidence ◽  
Virus Growth ◽  
Exact Function ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Herpes simplex virus (HSV) is characterized by its ability to establish a latent infection in sensory neurons, from which it can periodically reactivate. The mechanisms of latency, however, remain unclear. The HSV genome is quiescent during latency except for the expression of the latency-associated transcripts (LATs). Although the exact function of the LATs remains obscure, current evidence suggests they are multifunctional and are involved in both establishment of latency and reactivation from latency. The LATs contain several open reading frames (ORFs). One or more of the functions of the LATs could therefore be protein mediated. We have previously reported that deregulated expression of the largest of the HSV type 1 (HSV-1) LAT ORFs (∼274 amino acids) greatly enhances virus growth in cell types that are normally relatively nonpermissive for HSV replication and also that it complements mutations to the immediate-early (IE) gene ICP0 (S. K. Thomas, G. Gough, D. S. Latchman, and R. S. Coffin, J. Virol. 73:6618-6625, 1999). Here we show that LAT ORF expression overcomes the repression of expression from exogenous promoters introduced into the HSV-1 genome which normally occurs in the absence of IE gene expression. To further explore LAT ORF function, we have generated an epitope-tagged LAT ORF, LATmycHis, which forms punctate structures in the infected-cell nucleus reminiscent of the structures formed by ICP0. These are associated with the appearance of a phosphorylated form of the protein and are formed adjacent to, or around the edges of, viral replication compartments. These results provide further evidence that the HSV-1 LAT ORF protein is biologically functional and that the tightly regulated expression of this protein may be important in the wild-type latency phenotype in vivo.

scholarly journals Herpes Simplex Virus Type 1 Evades the Effects of Antibody and Complement In Vivo

2002 ◽  
Vol 76 (18) ◽  
pp. 9232-9241 ◽  
Author(s):  
John M. Lubinski ◽  
Ming Jiang ◽  
Lauren Hook ◽  
Yueh Chang ◽  
Chad Sarver ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Immune Evasion ◽  
Herpes Simplex Virus Type ◽  
Complement Components ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Herpes simplex virus type 1 (HSV-1) encodes a complement-interacting glycoprotein, gC, and an immunoglobulin G (IgG) Fc binding glycoprotein, gE, that mediate immune evasion by affecting multiple aspects of innate and acquired immunity, including interfering with complement components C1q, C3, C5, and properdin and blocking antibody-dependent cellular cytotoxicity. Previous studies evaluated the individual contributions of gC and gE to immune evasion. Experiments in a murine model that examines the combined effects of gC and gE immune evasion on pathogenesis are now reported. Virulence of wild-type HSV-1 is compared with mutant viruses defective in gC-mediated C3 binding, gE-mediated IgG Fc binding, or both immune evasion activities. Eliminating both activities greatly increased susceptibility of HSV-1 to antibody and complement neutralization in vitro and markedly reduced virulence in vivo as measured by disease scores, virus titers, and mortality. Studies with C3 knockout mice indicated that other activities attributed to these glycoproteins, such as gC-mediated virus attachment to heparan sulfate or gE-mediated cell-to-cell spread, do not account for the reduced virulence of mutant viruses. The results support the importance of gC and gE immune evasion in vivo and suggest potential new targets for prevention and treatment of HSV disease.

scholarly journals Antiviral effect of oryzacystatin, a proteinase inhibitor in rice, against herpes simplex virus type 1 in vitro and in vivo.

1995 ◽  
Vol 39 (4) ◽  
pp. 846-849 ◽  
Author(s):  
H Aoki ◽  
T Akaike ◽  
K Abe ◽  
M Kuroda ◽  
S Arai ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Rice Seed ◽  
Simplex Virus ◽  
Hsv 1

Oryzacystatin (OC) is the first-described cystatin originating from rice seed; it consists of two molecular species, OC-I and OC-II, which have antiviral action against poliovirus in vitro (H. Kondo, S. Ijiri, K. Abe, H. Maeda, and S. Arai, FEBS Lett. 299:48-50, 1992). In the experiments reported here, we investigated the effects of OC-I and OC-II on the replication of herpes simplex virus type 1 (HSV-1) in vitro and in vivo. HSV-1 was inoculated onto monolayers of monkey kidney epithelial cells (CV-1 cells) at a multiplicity of infection of 0.1 PFU per cell. After adsorption of the virus onto cells, the cultures were incubated in the presence of either OC-I or OC-II in the concentration range of 1.0 to 300 microM, and the supernatant virus yield was quantitated at 24 h. The effective concentration for 90% inhibition of HSV-1 was 14.8 microM, while a cytotoxic effect on CV-1 cells without infection of HSV-1 was not observed below 500 microM OC-I. Therefore, the apparent in vitro chemotherapeutic index was estimated to be more than 33. In the mouse model of HSV-1-induced keratitis and encephalopathy, topical administration of OC-I to the mouse cornea produced a significant decrease in virus production in the cornea (mean virus yields: 3.11 log10 PFU in the treated group and 4.37 log10 PFU in the control group) and significant improvement in survival rates (P = 0.01). The in vivo antiherpetic effect of OC-I was comparable to that of acyclovir, indicating that topical treatment of HSV-1 infection in humans with OC-I might be possible. Our data also suggest the importance of some thiol proteinases, which may be derived from either the host's cells or HSV-1, during the replication process of HSV-1.

scholarly journals Antiviral Activity of a Selective Ribonucleotide Reductase Inhibitor against Acyclovir-Resistant Herpes Simplex Virus Type 1 In Vivo

1998 ◽  
Vol 42 (7) ◽  
pp. 1629-1635 ◽  
Author(s):  
Jianmin Duan ◽  
Michel Liuzzi ◽  
William Paris ◽  
Michelle Lambert ◽  
Carol Lawetz ◽  
...  
Keyword(s):  
Drinking Water ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Ribonucleotide Reductase ◽  
Cutaneous Lesions ◽  
Athymic Nude Mice ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The present study reports the activity of BILD 1633 SE against acyclovir (ACV)-resistant herpes simplex virus (HSV) infections in athymic nude (nu/nu) mice. BILD 1633 SE is a novel peptidomimetic inhibitor of HSV ribonucleotide reductase (RR). In vitro, it is more potent than ACV against several strains of wild-type as well as ACV-resistant HSV mutants. Its in vivo activity was tested against cutaneous viral infections in athymic nude mice infected with the ACV-resistant isolates HSV type 1 (HSV-1) dlsptk and PAAr5, which contain mutations in the viral thymidine kinase gene and the polymerase gene, respectively. Following cutaneous infection of athymic nude mice, both HSV-1 dlsptk and PAAr5 induced significant, reproducible, and persistent cutaneous lesions that lasted for more than 2 weeks. A 10-day treatment regimen with ACV given topically four times a day as a 5% cream or orally at up to 5 mg/ml in drinking water was partially effective against HSV-1 PAAr5 infection with a reduction of the area under the concentration-time curve (AUC) of 34 to 48%. The effects of ACV against HSV-1 dlsptk infection were not significant when it was administered topically and were only marginal when it was given in drinking water. Treatment under identical conditions with 5% topical BILD 1633 SE significantly reduced the cutaneous lesions caused by both HSV-1 dlsptk and PAAr5 infections. The effect of BILD 1633 SE against HSV-1 PAAr5 infections was more prominent and was inoculum and dose dependent, with AUC reductions of 96 and 67% against infections with 106 and 107 PFU per inoculation site, respectively. BILD 1633 SE also significantly decreased the lesions caused by HSV-1dlsptk infection (28 to 51% AUC reduction). Combination therapy with topical BILD 1633 SE (5%) and ACV in drinking water (5 mg/ml) produced an antiviral effect against HSV-1 dlsptk and PAAr5 infections that was more than the sum of the effects of both drugs. This is the first report that a selective HSV RR subunit association inhibitor can be effective against ACV-resistant HSV infections in vivo.

scholarly journals Alpha/Beta Interferon and Gamma Interferon Synergize To Inhibit the Replication of Herpes Simplex Virus Type 1

2002 ◽  
Vol 76 (22) ◽  
pp. 11541-11550 ◽  
Author(s):  
Bruno Sainz ◽  
William P. Halford
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Vero Cells ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT In vivo evidence suggests that T-cell-derived gamma interferon (IFN-γ) can directly inhibit the replication of herpes simplex virus type 1 (HSV-1). However, IFN-γ is a weak inhibitor of HSV-1 replication in vitro. We have found that IFN-γ synergizes with the innate IFNs (IFN-α and -β) to potently inhibit HSV-1 replication in vitro and in vivo. Treatment of Vero cells with either IFN-β or IFN-γ inhibits HSV-1 replication by <20-fold, whereas treatment with both IFN-β and IFN-γ inhibits HSV-1 replication by ∼1,000-fold. Treatment with IFN-β and IFN-γ does not prevent HSV-1 entry into Vero cells, and the inhibitory effect can be overcome by increasing the multiplicity of HSV-1 infection. The capacity of IFN-β and IFN-γ to synergistically inhibit HSV-1 replication is not virus strain specific and has been observed in three different cell types. For two of the three virus strains tested, IFN-β and IFN-γ inhibit HSV-1 replication with a potency that approaches that achieved by a high dose of acyclovir. Pretreatment of mouse eyes with IFN-β and IFN-γ reduces HSV-1 replication to nearly undetectable levels, prevents the development of disease, and reduces the latent HSV-1 genome load per trigeminal ganglion by ∼200-fold. Thus, simultaneous activation of IFN-α/β receptors and IFN-γ receptors appears to render cells highly resistant to the replication of HSV-1. Because IFN-α or IFN-β is produced by most cells as an innate response to virus infection, the results imply that IFN-γ secreted by T cells may provide a critical second signal that potently inhibits HSV-1 replication in vivo.

scholarly journals In Vivo Ablation of CD11c-Positive Dendritic Cells Increases Susceptibility to Herpes Simplex Virus Type 1 Infection and Diminishes NK and T-Cell Responses

2006 ◽  
Vol 80 (8) ◽  
pp. 3985-3993 ◽  
Author(s):  
Sadik H. Kassim ◽  
Naveen K. Rajasagi ◽  
Xiangyi Zhao ◽  
Robert Chervenak ◽  
Stephen R. Jennings
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The precise role of each of the seven individual CD11c+ dendritic cell subsets (DCs) identified to date in the response to viral infections is not known. DCs serve as critical links between the innate and adaptive immune responses against many pathogens, including herpes simplex virus type 1 (HSV-1). The role of DCs as mediators of resistance to HSV-1 infection was investigated using CD11c-diphtheria toxin (DT) receptor-green fluorescent protein transgenic mice, in which DCs can be transiently depleted in vivo by treatment with low doses of DT. We show that ablation of DCs led to enhanced susceptibility to HSV-1 infection in the highly resistant C57BL/6 mouse strain. Specifically, we showed that the depletion of DCs led to increased viral spread into the nervous system, resulting in an increased rate of morbidity and mortality. Furthermore, we showed that ablation of DCs impaired the optimal activation of NK cells and CD4+ and CD8+ T cells in response to HSV-1. These data demonstrated that DCs were essential not only in the optimal activation of the acquired T-cell response to HSV-1 but also that DCs were crucial for innate resistance to HSV-1 infection.

scholarly journals In Vivo Changes in the Patterns of Chromatin Structure Associated with the Latent Herpes Simplex Virus Type 1 Genome in Mouse Trigeminal Ganglia Can Be Detected at Early Times after Butyrate Treatment

2007 ◽  
Vol 81 (23) ◽  
pp. 13248-13253 ◽  
Author(s):  
Donna M. Neumann ◽  
Partha S. Bhattacharjee ◽  
Nicole V. Giordani ◽  
David C. Bloom ◽  
James M. Hill
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Sodium Butyrate ◽  
Herpes Simplex Virus Type ◽  
Trigeminal Ganglia ◽  
Butyrate Treatment ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT During herpes simplex virus type 1 (HSV-1) latency in mouse dorsal root ganglia (DRG), chromatin associated with the latency-associated transcript (LAT) region of the viral genome is hyperacetylated at lysines 9 and 14 of histone 3 [H3(K9, K14)], while lytic genes are hypoacetylated. Explanted DRG exhibit a pattern of deacetylation of the LAT enhancer followed by acetylation of the ICP0 promoter at early times postexplant. Recently, we reported that sodium butyrate induced in vivo reactivation of HSV-1 in latent mice. In this study, we assessed the effect of sodium butyrate on the chromatin patterns of latent and butyrate-treated mouse trigeminal ganglia (TG) via chromatin immunoprecipitation (ChIP). We detected deacetylation of acetyl H3(K9, K14) of the LAT promoter and LAT enhancer regions as early as 0.5 h post-butyrate treatment, and this deacetylation corresponded to an increase in the acetylation of the lytic promoters ICP0 and ICP4 at 0.5 h and 1 h post-butyrate treatment, respectively. This is the first study to combine in vivo reactivation with the examination of the HSV-1 genome through ChIP assays at early times after the introduction of in vivo reactivation stimuli.

scholarly journals The ESCRT-Related ATPase Vps4 Is Modulated by Interferon during Herpes Simplex Virus 1 Infection

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Jorge Ruben Cabrera ◽  
Richard Manivanh ◽  
Brian J. North ◽  
David A. Leib
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Viral Infections ◽  
Cell Types ◽  
Primary Neurons ◽  
Herpes Simplex Virus 1 ◽  
Escrt Machinery ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTInterferons (IFNs) and autophagy are critical neuronal defenses against viral infection. IFNs alter neuronal autophagy by promoting the accumulation of IFN-dependent LC3-decorated autophagic structures, termed LC3 clusters. Here, we analyzed LC3 clusters in sensory ganglia following herpes simplex virus 1 (HSV-1) infection. In the vicinity of acutely infected neurons, antigen-negative neurons contained structures resembling accumulated autophagosomes and autolysosomes that culminated in LC3 clusters. This accumulation reflects a delayed completion of autophagy. Theendosomalsortingcomplexesrequired fortransport (ESCRT) machinery participates in autophagosome closure and is also required for HSV-1 replication. In this study, our results showed that HSV-1 infectionin vivoand in primary neurons caused a decrease in Vps4 (a key ESCRT pathway ATPase) RNA and protein with concomitant Stat1 activation and LC3 cluster induction. We also observed that IFNs were sufficient to decrease RNA and protein levels of Vps4 in primary neurons and in other cell types. The accumulation of ubiquitin was also observed at the LC3 cluster sites. Together, our results show that IFNs modulate the ESCRT machinery in neurons in response to HSV-1 infections.IMPORTANCENeurons rely on IFNs and autophagy as major defenses against viral infections, and HSV must overcome such defenses in order to replicate. In addition to controlling host immunity, HSV must also control host membranes in order to complete its life cycle. HSV uses the host ESCRT membrane scission machinery for viral production and transport. Here we present evidence of a new IFN-dependent mechanism used by the host to prevent ESCRT subversion by HSV. This activity also impacts the dynamics of autophagy, possibly explaining the presence of recently described LC3 clusters in the HSV-infected nervous system. The induced accumulations of ubiquitin observed in these LC3 clusters resembled those observed in certain neurodegenerative diseases, suggesting possible mechanistic parallels between these conditions.

scholarly journals Dendritic Cells Are Required for Optimal Activation of Natural Killer Functions following Primary Infection with Herpes Simplex Virus Type 1

2009 ◽  
Vol 83 (7) ◽  
pp. 3175-3186 ◽  
Author(s):  
Sadik H. Kassim ◽  
Naveen K. Rajasagi ◽  
Barry W. Ritz ◽  
Stephen B. Pruett ◽  
Elizabeth M. Gardner ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Nk Cells ◽  
Nk Cell ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Natural killer (NK) cells play an important role in the optimal clearance of herpes simplex virus type 1 (HSV-1) infection in mice. Activated NK cells function via cytokine secretion or direct cytolysis of target cells; dendritic cells (DCs) are thought to make critical contributions in the activation of both of these functions. Yet, the magnitude and physiological relevance of DC-mediated NK cell activation in vivo is not completely understood. To examine the contribution of DC help in regulating NK cell functions after infection with HSV-1, we utilized a transgenic mouse model that allows the transient ablation of DCs. Using this approach, it was found that the gamma interferon (IFN-γ) expression potential of NK cells is quantitatively and qualitatively impaired in the absence of DCs. With regard to priming of NK cytolytic functions, the ablation of DCs did not significantly affect cytotoxic protein expression by NK cells. An in vivo cytolytic assay did, however, reveal impairments in the magnitude of NK cell cytotoxicity. Overall, this study provides direct evidence that functional DCs are required for optimal IFN-γ expression and cytolytic function by NK cells following infection with HSV-1.

scholarly journals Dot1l Aggravates Keratitis Induced by Herpes Simplex Virus Type 1 in Mice via p38 MAPK-Mediated Oxidative Stress

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Shanshan Wan ◽  
Yiwen Zhou ◽  
Qiong Huang ◽  
Yanning Yang
Keyword(s):  
Oxidative Stress ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
P38 Mapk ◽  
Herpes Simplex Virus Type ◽  
Simplex Virus ◽  
Hsv 1

Background. Disruptor of telomeric silencing 1-like (Dot1l) plays a vital role in biological processes as a well-known methyltransferase. However, its role in herpes simplex virus type 1- (HSV-1-) infected keratitis remains unclear. Methods. In vitro and in vivo models were assessed to investigate the role of Dot1l in HSV-1 induced keratitis. C57BL/6 mice corneas were infected with HSV-1 for different days, with or without Dot1l inhibitor, to demonstrate the regulation of Dot1l in herpes simplex keratitis (HSK). Human corneal epithelial (HCE) cells were cultured and infected with HSV-1 to identify the molecular mechanisms involved. Results. In this study, we found that Dot1l was positively related to HSK. Inhibition of Dot1l with EPZ004777 (EPZ) alleviated corneal injury, including oxidative stress and inflammation in vivo. Similarly, the inhibition of Dot1l with either EPZ or small interfering RNA (siRNA) showed an inhibitory effect on HSV-1-induced oxidative stress and inflammation in HCE cells. Moreover, our study revealed that the expression of p38 MAPK was elevated after HSV-1 infection in HCE cells, and the inhibition of Dot1l could reduce the increased expression of p38 MAPK induced by HSV-1 infection in vivo and in vitro. Conclusion. Our results demonstrated that the inhibition of Dot1l alleviated corneal oxidative stress and inflammation by inhibiting ROS production through the p38 MAPK pathway in HSK. These findings indicated that Dot1l might be a valuable therapeutic target for HSK.

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