Evaluation of a peptidomimetic ribonucleotide reductase inhibitor with a murine model of herpes simplex virus type 1 ocular disease.

The ribonucleotide reductase (RR) of herpes simplex virus type 1 (HSV-1) is an important virulence factor, being required for neurovirulence, ocular virulence, and reactivation from latency. The RR activity requires the association of two distinct homodimeric subunits, and the association of the subunits is inhibited in the presence of a peptide homologous to the carboxy terminus of the small subunit. A structural analog of the inhibitory peptide (BILD 1263) has been shown to inhibit the replication of HSV-1 at micromolar concentrations in vitro. We used a mouse model of HSV-1 ocular infection to determine the in vivo efficacy of topical BILD 1263. Treatment of HSV-1 KOS-infected mice resulted in significant reductions in the severity and incidence of stromal keratitis and corneal neovascularization. At higher concentrations (5%) BILD 1263 reduced the severity but not the incidence of blepharitis. Treatment with 5% BILD 1263 also reduced viral shedding from the cornea by 10- to 14-fold (P < 0.001). In uninfected mice treated with 5% BILD 1263, we found no evidence of corneal epithelial damage, conjunctivitis, or blepharitis, and histopathological studies revealed no changes in the corneas of these mice. These results show that the peptidomimetic RR inhibitor BILD 1263 is effective in preventing disease, has an antiviral effect in vivo, and has little or no toxicity.

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

Journal of Virology ◽

10.1128/jvi.76.18.9232-9241.2002 ◽

2002 ◽

Vol 76 (18) ◽

pp. 9232-9241 ◽

Cited By ~ 63

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.39.4.846 ◽

1995 ◽

Vol 39 (4) ◽

pp. 846-849 ◽

Cited By ~ 41

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.

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Abnormal immune response of CCR5-deficient mice to ocular infection with herpes simplex virus type 1

Journal of General Virology ◽

10.1099/vir.0.81339-0 ◽

2006 ◽

Vol 87 (3) ◽

pp. 489-499 ◽

Cited By ~ 37

Author(s):

Daniel J. J. Carr ◽

John Ash ◽

Thomas E. Lane ◽

William A. Kuziel

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Trigeminal Ganglion ◽

Herpes Simplex Virus Type ◽

Ocular Infection ◽

Compensatory Mechanisms ◽

Simplex Virus ◽

Hsv 1

Ocular herpes simplex virus type 1 (HSV-1) infection elicits a strong inflammatory response that is associated with production of the β chemokines CCL3 and CCL5, which share a common receptor, CCR5. To gain insight into the role of these molecules in ocular immune responses, the corneas of wild-type (WT) and CCR5-deficient (CCR5−/−) mice were infected with HSV-1 and inflammatory parameters were measured. In the absence of CCR5, the early infiltration of neutrophils into the cornea was diminished. Associated with this aberrant leukocyte recruitment, neutrophils in CCR5−/− mice were restricted to the stroma, whereas in WT mice, these cells trafficked to the stroma and epithelial layers of the infected cornea. Virus titres and cytokine/chemokine levels in the infected tissue of these mice were similar for the first 5 days after infection. However, by day 7 post-infection, the CCR5−/− mice showed a significant elevation in the chemokines CCL2, CCL5, CXCL9 and CXCL10 in the trigeminal ganglion and brainstem, as well as a significant increase in virus burden. The increase in chemokine expression was associated with an increase in the infiltration of CD4 and/or CD8 T cells into the trigeminal ganglion and brainstem of CCR5−/− mice. Surprisingly, even though infected CCR5−/− mice were less efficient at controlling the progression of virus replication, there was no difference in mortality. These results suggest that, although CCR5 plays a role in regulating leukocyte trafficking and control of virus burden, compensatory mechanisms are involved in preventing mortality following HSV-1 infection.

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

Journal of Virology ◽

10.1128/jvi.80.8.3985-3993.2006 ◽

2006 ◽

Vol 80 (8) ◽

pp. 3985-3993 ◽

Cited By ~ 91

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.

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A Herpes Simplex Virus Type 1 Latency-Associated Transcript Mutant with Increased Virulence and Reduced Spontaneous Reactivation

Journal of Virology ◽

10.1128/jvi.73.2.920-929.1999 ◽

1999 ◽

Vol 73 (2) ◽

pp. 920-929 ◽

Cited By ~ 40

Author(s):

Guey-Chuen Perng ◽

Susan M. Slanina ◽

Ada Yukht ◽

Barbara S. Drolet ◽

William Keleher ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Ocular Infection ◽

Wild Type ◽

Simplex Virus ◽

Spontaneous Reactivation ◽

Hsv 1

ABSTRACT The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) gene is essential for efficient spontaneous reactivation of HSV-1 from latency. We previously reported that insertion of the LAT promoter and just the first 1.5 kb of the 8.3-kb LAT gene into an ectopic location in the virus restored wild-type spontaneous reactivation to a LAT null mutant. This mutant, LAT3.3A (previously designated LAT1.5a), thus showed that the expression of just the first 1.5 kb of LAT is sufficient for wild-type spontaneous reactivation. We also showed that in the context of the entire LAT gene, deletion of LAT nucleotides 76 to 447 (LAT mutantdLAT371) had no effect on spontaneous reactivation or virulence. We report here on a LAT mutant designated LAT2.9A. This mutant is similar to LAT3.3A, except that the ectopic LAT insert contains the same 371-nucleotide deletion found in dLAT371. We found that LAT2.9A had a significantly reduced rate of spontaneous reactivation compared to marker-rescued and wild-type viruses. This was unexpected, since the combined results of dLAT371 and LAT3.3A predicted that spontaneous reactivation of LAT2.9A would be wild type. We also found that LAT2.9A was more virulent than wild-type or marker-rescued viruses after ocular infection of rabbits. This was unexpected, since LAT null mutants and LAT3.3A have wild-type virulence. These results suggest for the first time (i) that regions past the first 1.5 kb of LAT can compensate for deletions in the first 1.5kb of LAT and may therefore play a role in LAT dependent spontaneous reactivation and (ii) that regions of LAT affect viral virulence.

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A Cationic Peptide, TAT-Cd0, Inhibits Herpes Simplex Virus Type 1 Ocular Infection In Vivo

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.12-10250 ◽

2013 ◽

Vol 54 (2) ◽

pp. 1070 ◽

Cited By ~ 11

Author(s):

Gilbert G. Jose ◽

Inna V. Larsen ◽

Joshua Gauger ◽

Erica Carballo ◽

Rebecca Stern ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Ocular Infection ◽

Cationic Peptide ◽

Simplex Virus

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Delection of the herpes simplex virus type 1 ribonucleotide reductase gene alters virulence and latency in vivo

Antiviral Research ◽

10.1016/0166-3542(92)90048-a ◽

1992 ◽

Vol 17 (2) ◽

pp. 145-156 ◽

Cited By ~ 42

Author(s):

Arit D. Idowu ◽

Elizabeth B. Fraser-Smith ◽

Kimber L. Poffenberger ◽

Ronald C. Herman

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Ribonucleotide Reductase ◽

Herpes Simplex Virus Type ◽

Reductase Gene ◽

Simplex Virus

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The Latency-Associated Transcript Gene Enhances Establishment of Herpes Simplex Virus Type 1 Latency in Rabbits

Journal of Virology ◽

10.1128/jvi.74.4.1885-1891.2000 ◽

2000 ◽

Vol 74 (4) ◽

pp. 1885-1891 ◽

Cited By ~ 79

Author(s):

Guey-Chuen Perng ◽

Susan M. Slanina ◽

Ada Yukht ◽

Homayon Ghiasi ◽

Anthony B. Nesburn ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Fluorescent Protein ◽

Ocular Infection ◽

Latently Infected ◽

Simplex Virus ◽

Hsv 1

ABSTRACT The latency-associated transcript (LAT) gene the only herpes simplex virus type 1 (HSV-1) gene abundantly transcribed during neuronal latency, is essential for efficient in vivo reactivation. Whether LAT increases reactivation by a direct effect on the reactivation process or whether it does so by increasing the establishment of latency, thereby making more latently infected neurons available for reactivation, is unclear. In mice, LAT-negative mutants appear to establish latency in fewer neurons than does wild-type HSV-1. However, this has not been confirmed in the rabbit, and the role of LAT in the establishment of latency remains controversial. To pursue this question, we inserted the gene for the enhanced green fluorescent protein (EGFP) under control of the LAT promoter in a LAT-negative virus (ΔLAT-EGFP) and in a LAT-positive virus (LAT-EGFP). Sixty days after ocular infection, trigeminal ganglia (TG) were removed from the latently infected rabbits, sectioned, and examined by fluorescence microscopy. EGFP was detected in significantly more LAT-EGFP-infected neurons than ΔLAT-EGFP-infected neurons (4.9% versus 2%, P < 0.0001). The percentages of EGFP-positive neurons per TG ranged from 0 to 4.6 for ΔLAT-EGFP and from 2.5 to 11.1 for LAT-EGFP (P = 0.003). Thus, LAT appeared to increase neuronal latency in rabbit TG by an average of two- to threefold. These results suggest that LAT enhances the establishment of latency in rabbits and that this may be one of the mechanisms by which LAT enhances spontaneous reactivation. These results do not rule out additional LAT functions that may be involved in maintenance of latency and/or reactivation from latency.

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