scholarly journals 6-Thioguanine Inhibits Herpes Simplex Virus 1 Infection of Eyes

2021 ◽  
Author(s):  
Deyan Chen ◽  
Ye Liu ◽  
Fang Zhang ◽  
Qiao You ◽  
Wenyuan Ma ◽  
...  
Keyword(s):  
Animal Model ◽  
Herpes Simplex ◽  
Resistant Mutant ◽  
Herpes Simplex Virus 1 ◽  
Model Studies ◽  
Simplex Virus ◽  
Potent Inhibitory Activity ◽  
Hsv 1

We reported the discovery of 6-TG inhibition of HSV-1 infection and its inhibitory roles in HSK both in vitro and in vivo . 6-TG was shown to possess at least 10× more potent inhibitory activity against HSV-1 than ACV and GCV and, more importantly, inhibit ACV/GCV-resistant mutant viruses. Animal model studies showed that gel-formulated 6-TG topically applied to eyes locally infected with HSV-1 could significantly inhibit HSV-1 replication, alleviate virus-induced HSK pathogenesis, and improve eye conditions.

scholarly journals Structural Variability of the Herpes Simplex Virus 1 GenomeIn VitroandIn Vivo

2012 ◽  
Vol 86 (16) ◽  
pp. 8592-8601 ◽  
Author(s):  
Charlotte Mahiet ◽  
Ayla Ergani ◽  
Nicolas Huot ◽  
Nicolas Alende ◽  
Ahmed Azough ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Considerable Proportion ◽  
Inverted Repeats ◽  
Herpes Simplex Virus 1 ◽  
Cell Extracts ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus 1 (HSV-1) is a human pathogen that leads to recurrent facial-oral lesions. Its 152-kb genome is organized in two covalently linked segments, each composed of a unique sequence flanked by inverted repeats. Replication of the HSV-1 genome produces concatemeric molecules in which homologous recombination events occur between the inverted repeats. This mechanism leads to four genome isomers (termed P, IS, IL, and ILS) that differ in the relative orientations of their unique fragments. Molecular combing analysis was performed on DNA extracted from viral particles and BSR, Vero, COS-7, and Neuro-2a cells infected with either strain SC16 or KOS of HSV-1, as well as from tissues of experimentally infected mice. Using fluorescence hybridization, isomers were repeatedly detected and distinguished and were accompanied by a large proportion of noncanonical forms (40%). In both cell and viral-particle extracts, the distributions of the four isomers were statistically equivalent, except for strain KOS grown in Vero and Neuro-2a cells, in which P and IS isomers were significantly overrepresented. In infected cell extracts, concatemeric molecules as long as 10 genome equivalents were detected, among which, strikingly, the isomer distributions were equivalent, suggesting that any such imbalance may occur during encapsidation.In vivo, for strain KOS-infected trigeminal ganglia, an unbalanced distribution distinct from the onein vitrowas observed, along with a considerable proportion of noncanonical assortment.

scholarly journals Restoring Herpesvirus Entry Mediator (HVEM) Immune Function in HVEM−/− Mice Rescues Herpes Simplex Virus 1 Latency and Reactivation Independently of Binding to Glycoprotein D

2020 ◽  
Vol 94 (16) ◽  
Author(s):  
Kati Tormanen ◽  
Shaohui Wang ◽  
Ujjaldeep Jaggi ◽  
Homayon Ghiasi
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Function ◽  
Interleukin 2 ◽  
Glycoprotein D ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The immune modulatory protein herpes virus entry mediator (HVEM) is one of several cellular receptors used by herpes simplex virus 1 (HSV-1) for cell entry. HVEM binds to HSV-1 glycoprotein D (gD) but is not necessary for HSV-1 replication in vitro or in vivo. Previously, we showed that although HSV-1 replication was similar in wild-type (WT) control and HVEM−/− mice, HSV-1 does not establish latency or reactivate effectively in mice lacking HVEM, suggesting that HVEM is important for these functions. It is not known whether HVEM immunomodulatory functions contribute to latency and reactivation or whether its binding to gD is necessary. We used HVEM−/− mice to establish three transgenic mouse lines that express either human WT HVEM or human or mouse HVEM with a point mutation that ablates its ability to bind to gD. Here, we show that HVEM immune function, not its ability to bind gD, is required for WT levels of latency and reactivation. We further show that HVEM binding to gD does not affect expression of the HVEM ligands BTLA, CD160, or LIGHT. Interestingly, our results suggest that binding of HVEM to gD may contribute to efficient upregulation of CD8α but not PD1, TIM-3, CTLA4, or interleukin 2 (IL-2). Together, our results establish that HVEM immune function, not binding to gD, mediates establishment of latency and reactivation. IMPORTANCE HSV-1 is a common cause of ocular infections worldwide and a significant cause of preventable blindness. Corneal scarring and blindness are consequences of the immune response induced by repeated reactivation events. Therefore, HSV-1 therapeutic approaches should focus on preventing latency and reactivation. Our data suggest that the immune function of HVEM plays an important role in the HSV-1 latency and reactivation cycle that is independent of HVEM binding to gD.

scholarly journals CD80 Plays a Critical Role in Increased Inflammatory Responses in Herpes Simplex Virus 1-Infected Mouse Corneas

2019 ◽  
Vol 94 (2) ◽  
Author(s):  
Kati Tormanen ◽  
Shaohui Wang ◽  
Homayon Ghiasi
Keyword(s):  
T Cells ◽  
Herpes Simplex ◽  
Parental Virus ◽  
Eye Disease ◽  
Herpes Simplex Virus 1 ◽  
Corneal Scarring ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT We recently reported that herpes simplex virus 1 (HSV-1) infection suppresses CD80 but not CD86 expression in vitro and in vivo. This suppression required the HSV-1 ICP22 gene. We also reported that overexpression of CD80 by HSV-1 exacerbated corneal scarring in BALB/c mice. We now show that this recombinant virus (HSV-CD80) expressed high levels of CD80 both in vitro in cultured rabbit skin cells and in vivo in infected mouse corneas. CD80 protein was detected on the surface of infected cells. The virulence of the recombinant HSV-CD80 virus was similar to that of the parental strain, and the replication of HSV-CD80 was similar to that of control virus in vitro and in vivo. Transcriptome analysis detected 75 known HSV-1 genes in the corneas of mice infected with HSV-CD80 or parental virus on day 4 postinfection. Except for significantly higher CD80 expression in HSV-CD80-infected mice, levels of HSV-1 gene expression were similar in corneas from HSV-CD80-infected and parental virus-infected mice. The number of CD8+ T cells was higher, and the number of CD4+ T cells was lower, in the corneas of HSV-CD80-infected mice than in mice infected with parental virus. HSV-CD80-infected mice displayed a transient increase in dendritic cells. Transcriptome analysis revealed mild differences in dendritic cell maturation and interleukin-1 signaling pathways and increased expression of interferon-induced protein with tetratricopeptide repeats 2 (Ifit2). Together, these results suggest that increased CD80 levels promote increased CD8+ T cells, leading to exacerbated eye disease in HSV-1-infected mice. IMPORTANCE HSV-1 ocular infections are the leading cause of corneal blindness. Eye disease is the result of a prolonged immune response to the replicating virus. HSV-1, on the other hand, has evolved several mechanisms to evade clearance by the host immune system. We describe a novel mechanism of HSV-1 immune evasion via ICP22-dependent downregulation of the host T cell costimulatory molecule CD80. However, the exact role of CD80 in HSV-1 immune pathology is not clear. In this study, we show that eye disease is independent of the level of HSV-1 replication and that viral expression of CD80 has a detrimental role in corneal scarring, likely by increasing CD8+ T cell recruitment and activation.

scholarly journals A novel bioluminescent herpes simplex virus 1 for in vivo monitoring of herpes simplex encephalitis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Olus Uyar ◽  
Pier-Luc Plante ◽  
Jocelyne Piret ◽  
Marie-Christine Venable ◽  
Julie Carbonneau ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cell Culture Supernatant ◽  
Herpes Simplex Virus Encephalitis ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1 ◽  
Viral Titers

AbstractHerpes simplex virus 1 (HSV-1) is responsible for herpes simplex virus encephalitis (HSE), associated with a 70% mortality rate in the absence of treatment. Despite intravenous treatment with acyclovir, mortality remains significant, highlighting the need for new anti-herpetic agents. Herein, we describe a novel neurovirulent recombinant HSV-1 (rHSV-1), expressing the fluorescent tdTomato and Gaussia luciferase (Gluc) enzyme, generated by the Clustered regularly interspaced short palindromic repeats (CRISPR)—CRISPR-associated protein 9 (Cas9) (CRISPR-Cas9) system. The Gluc activity measured in the cell culture supernatant was correlated (P = 0.0001) with infectious particles, allowing in vitro monitoring of viral replication kinetics. A significant correlation was also found between brain viral titers and Gluc activity in plasma (R2 = 0.8510, P < 0.0001) collected from BALB/c mice infected intranasally with rHSV-1. Furthermore, evaluation of valacyclovir (VACV) treatment of HSE could also be performed by analyzing Gluc activity in mouse plasma samples. Finally, it was also possible to study rHSV-1 dissemination and additionally to estimate brain viral titers by in vivo imaging system (IVIS). The new rHSV-1 with reporter proteins is not only as a powerful tool for in vitro and in vivo antiviral screening, but can also be used for studying different aspects of HSE pathogenesis.

scholarly journals Persistent Infection with Herpes Simplex Virus 1 and Alzheimer’s Disease—A Call to Study How Variability in Both Virus and Host may Impact Disease

Viruses ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 966 ◽  
Author(s):  
Colleen A. Mangold ◽  
Moriah L. Szpara
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Future Research ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

Increasing attention has focused on the contributions of persistent microbial infections with the manifestation of disease later in life, including neurodegenerative conditions such as Alzheimer’s disease (AD). Current data has shown the presence of herpes simplex virus 1 (HSV-1) in regions of the brain that are impacted by AD in elderly individuals. Additionally, neuronal infection with HSV-1 triggers the accumulation of amyloid beta deposits and hyperphosphorylated tau, and results in oxidative stress and synaptic dysfunction. All of these factors are implicated in the development of AD. These data highlight the fact that persistent viral infection is likely a contributing factor, rather than a sole cause of disease. Details of the correlations between HSV-1 infection and AD development are still just beginning to emerge. Future research should investigate the relative impacts of virus strain- and host-specific factors on the induction of neurodegenerative processes over time, using models such as infected neurons in vitro, and animal models in vivo, to begin to understand their relationship with cognitive dysfunction.

scholarly journals The US11 Gene of Herpes Simplex Virus 1 Promotes Neuroinvasion and Periocular Replication following Corneal Infection

2019 ◽  
Vol 93 (9) ◽  
Author(s):  
Audra J. Charron ◽  
Stephen L. Ward ◽  
Brian J. North ◽  
Stacey Ceron ◽  
David A. Leib
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Trigeminal Ganglia ◽  
Herpes Simplex Virus 1 ◽  
Corneal Infection ◽  
Simplex Virus ◽  
Phosphorylated Eif2α ◽  
Hsv 1

ABSTRACTHerpes simplex virus 1 (HSV-1) cycles between phases of latency in sensory neurons and replication in mucosal sites. HSV-1 encodes two key proteins that antagonize the shutdown of host translation, US11 through preventing PKR activation and ICP34.5 through mediating dephosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). While profound attenuation of ICP34.5 deletion mutants has been repeatedly demonstrated, a role for US11 in HSV-1 pathogenesis remains unclear. We therefore generated an HSV-1 strain 17 US11-null virus and examined its propertiesin vitroandin vivo. In U373 glioblastoma cells, US11 cooperated with ICP34.5 to prevent eIF2α phosphorylation late in infection. However, the effect was muted in human corneal epithelial cells (HCLEs), which did not accumulate phosphorylated eIF2α unless both US11 and ICP34.5 were absent. Low levels of phosphorylated eIF2α correlated with continued protein synthesis and with the ability of virus lacking US11 to overcome antiviral immunity in HCLE and U373 cells. Neurovirulence following intracerebral inoculation of mice was not affected by the deletion of US11. In contrast, the time to endpoint criteria following corneal infection was greater for the US11-null virus than for the wild-type virus. Replication in trigeminal ganglia and periocular tissue was promoted by US11, as was periocular disease. The establishment of latency and the frequency of virus reactivation from trigeminal ganglia were unaffected by US11 deletion, although emergence of the US11-null virus occurred with slowed kinetics. Considered together, the data indicate that US11 facilitates the countering of antiviral response of infected cells and promotes the efficient emergence of virus following reactivation.IMPORTANCEAlphaherpesviruses are ubiquitous DNA viruses and include the human pathogens herpes simplex virus 1 (HSV-1) and HSV-2 and are significant causes of ulcerative mucosal sores, infectious blindness, encephalitis, and devastating neonatal disease. Successful primary infection and persistent coexistence with host immune defenses are dependent on the ability of these viruses to counter the antiviral response. HSV-1 and HSV-2 and other primate viruses within theSimplexvirusgenus encode US11, an immune antagonist that promotes virus production by preventing shutdown of protein translation. Here we investigated the impact of US11 deletion on HSV-1 growthin vitroand pathogenesisin vivo. This work supports a role for US11 in pathogenesis and emergence from latency, elucidating immunomodulation by this medically important cohort of viruses.

scholarly journals Antiviral Activity of the G-Quadruplex Ligand TMPyP4 against Herpes Simplex Virus-1

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 196
Author(s):  
Sara Artusi ◽  
Emanuela Ruggiero ◽  
Matteo Nadai ◽  
Beatrice Tosoni ◽  
Rosalba Perrone ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Dna Replication ◽  
Herpes Simplex ◽  
Antiviral Activity ◽  
Herpes Simplex Virus 1 ◽  
Tem Analysis ◽  
Infected Cells ◽  
Simplex Virus ◽  
Hsv 1

The herpes simplex virus 1 (HSV-1) genome is extremely rich in guanine tracts that fold into G-quadruplexes (G4s), nucleic acid secondary structures implicated in key biological functions. Viral G4s were visualized in HSV-1 infected cells, with massive virus cycle-dependent G4-formation peaking during viral DNA replication. Small molecules that specifically interact with G4s have been shown to inhibit HSV-1 DNA replication. We here investigated the antiviral activity of TMPyP4, a porphyrin known to interact with G4s. The analogue TMPyP2, with lower G4 affinity, was used as control. We showed by biophysical analysis that TMPyP4 interacts with HSV-1 G4s, and inhibits polymerase progression in vitro; in infected cells, it displayed good antiviral activity which, however, was independent of inhibition of virus DNA replication or entry. At low TMPyP4 concentration, the virus released by the cells was almost null, while inside the cell virus amounts were at control levels. TEM analysis showed that virus particles were trapped inside cytoplasmatic vesicles, which could not be ascribed to autophagy, as proven by RT-qPCR, western blot, and immunofluorescence analysis. Our data indicate a unique mechanism of action of TMPyP4 against HSV-1, and suggest the unprecedented involvement of currently unknown G4s in viral or antiviral cellular defense pathways.

scholarly journals Healing of Ocular Herpetic Disease Following Treatment With an Engineered FGF-1 Is Associated With Increased Corneal Anti-Inflammatory M2 Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Nisha R. Dhanushkodi ◽  
Ruchi Srivastava ◽  
Pierre-Gregoire A. Coulon ◽  
Swayam Prakash ◽  
Soumyabrata Roy ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Herpes Simplex Virus 1 ◽  
Cytokines And Chemokines ◽  
Latently Infected ◽  
Stromal Keratitis ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus 1 (HSV-1) infects the cornea and caused blinding ocular disease. In the present study, we evaluated whether and how a novel engineered version of fibroblast growth factor-1 (FGF-1), designated as TTHX1114, would reduce the severity of HSV-1-induced and recurrent ocular herpes in the mouse model. The efficacy of TTHX1114 against corneal keratopathy was assessed in B6 mice following corneal infection with HSV-1, strain McKrae. Starting day one post infection (PI), mice received TTHX1114 for 14 days. The severity of primary stromal keratitis and blepharitis were monitored up to 28 days PI. Inflammatory cell infiltrating infected corneas were characterized up to day 21 PI. The severity of recurrent herpetic disease was quantified in latently infected B6 mice up to 30 days post-UVB corneal exposure. The effect of TTHX1114 on M1 and M2 macrophage polarization was determined in vivo in mice and in vitro on primary human monocytes-derived macrophages. Compared to HSV-1 infected non-treated mice, the infected and TTHX1114 treated mice exhibited significant reduction of primary and recurrent stromal keratitis and blepharitis, without affecting virus corneal replication. The therapeutic effect of TTHX1114 was associated with a significant decrease in the frequency of M1 macrophages infiltrating the cornea, which expressed significantly lower levels of pro-inflammatory cytokines and chemokines. This polarization toward M2 phenotype was confirmed in vitro on human primary macrophages. This pre-clinical finding suggests use of this engineered FGF-1 as a novel immunotherapeutic regimen to reduce primary and recurrent HSV-1-induced corneal disease in the clinic.

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 Cell-to-Cell Spread Blocking Activity Is Extremely Limited in the Sera of Herpes Simplex Virus 1 (HSV-1)- and HSV-2-Infected Subjects

2019 ◽  
Vol 93 (11) ◽  
Author(s):  
Elena Criscuolo ◽  
Matteo Castelli ◽  
Roberta A. Diotti ◽  
Virginia Amato ◽  
Roberto Burioni ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Humoral Immunity ◽  
Virus Entry ◽  
Serum Antibody ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTHerpes simplex virus 1 (HSV-1) and HSV-2 can evade serum antibody-mediated neutralization through cell-to-cell transmission mechanisms, which represent one of the central steps in disease reactivation. To address the role of humoral immunity in controlling HSV-1 and HSV-2 replication, we analyzed serum samples from 44 HSV-1 and HSV-2 seropositive subjects by evaluating (i) their efficiency in binding both the purified viral particles and recombinant gD and gB viral glycoproteins, (ii) their neutralizing activity, and (iii) their capacity to inhibit the cell-to-cell virus passagein vitro. All of the sera were capable of binding gD, gB, and whole virions, and all sera significantly neutralized cell-free virus. However, neither whole sera nor purified serum IgG fraction was able to inhibit significantly cell-to-cell virus spreading inin vitropost-virus-entry infectious assays. Conversely, when spiked with an already described anti-gD human monoclonal neutralizing antibody capable of inhibiting HSV-1 and -2 cell-to-cell transmission, each serum boosted both its neutralizing and post-virus-entry inhibitory activity, with no interference exerted by serum antibody subpopulations.IMPORTANCEDespite its importance in the physiopathology of HSV-1 and -2 infections, the cell-to-cell spreading mechanism is still poorly understood. The data shown here suggest that infection-elicited neutralizing antibodies capable of inhibiting cell-to-cell virus spread can be underrepresented in most infected subjects. These observations can be of great help in better understanding the role of humoral immunity in controlling virus reactivation and in the perspective of developing novel therapeutic strategies, studying novel correlates of protection, and designing effective vaccines.

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