Ocular herpes simplex virus: how are latency, reactivation, recurrent disease and therapy interrelated?

Most humans are infected with herpes simplex virus (HSV) type 1 in early childhood and remain latently infected throughout life. While most individuals have mild or no symptoms, some will develop destructive HSV keratitis. Ocular infection with HSV-1 and its associated sequelae account for the majority of corneal blindness in industrialized nations.

In vitro synergism of trifluorothymidine and ganciclovir against HSV-1.

Purpose: To determine whether trifluorothymidine (TFT) and ganciclovir (GCV) are synergistic against herpes simplex virus type 1 (HSV-1).

Methods: TFT and GCV activity against 12 strains of HSV-1 (including an acyclovir-resistant strain) was measured by plaque-forming unit (PFU) inhibition. Cellular toxicity was assessed with an MTT dye reduction assay.

Effect of high versus low oral doses of valacyclovir on herpes simplex virus-1 DNA shedding into tears of latently infected rabbits.

Purpose: To assess the effect of high doses of valacyclovir (VCV) on HSV-1 DNA shedding into tears of latently infected rabbits.

Methods: Three oral doses of VCV were tested. Corneas were inoculated with HSV-1, and latent infection was allowed to establish.

A double-blind placebo-controlled study to evaluate valacyclovir alone and with aspirin for asymptomatic HSV-1 DNA shedding in human tears and saliva.

Purpose: To test the effect of valacyclovir alone and with aspirin on the asymptomatic shedding of HSV-1 DNA in tears and saliva of healthy individuals. METHOD. The subjects (n = 45) were randomized into three groups without regard to age, sex, or race.

WITHDRAWN: Synergistic interaction of aciclovir and a helicase-primase inhibitor, BAY 57-1293, against herpes simplex virus type 1.

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Efficacy of a helicase-primase inhibitor in animal models of ocular herpes simplex virus type 1 infection.

Purpose: The aim of this study was to evaluate the effect of BAY 57-1293, a helicase-primase inhibitor, on herpes simplex virus type 1 (HSV-1) reactivation in mice and its efficacy on established disease in rabbits.

Methods: BALB/c mice latent for McKrae-strain HSV-1 were reactivated via heat stress, treated with BAY 57-1293, and their corneas were swabbed for virus or the trigeminal ganglia (TG) obtained for quantification of viral DNA. New Zealand white rabbits were infected and treated topically or orally in comparison with trifluridine or valacyclovir.

Preliminary in vitro evaluation of 2-octyl cyanoacrylate (Dermabond) to seal corneal incisions.

Objective: To compare the efficacy of Dermabond with conventional nylon sutures for sealing linear corneal incisions.

Methods: A keratome knife was used to create a 4-mm full-thickness linear corneal incision anterior to the limbal arcade in 20 fresh pig eyes. The incision was sealed with Dermabond tissue adhesive or closed with 10-0 nylon sutures.

Immunohistochemical analysis of orbital connective tissue specimens of patients with active Graves ophthalmopathy.

Purpose: To explore the immune mechanism of Graves ophthalmopathy (GO) by analyzing infiltrating cells in orbital connective tissue (OCT) specimens of patients with active GO using immunohistochemical methods.

Methods: Five OCT specimens obtained from patients with active GO and five control specimens obtained from forensic cadavers who died from nonmedical reasons were stained with anti-CD3, CD4, CD8, CD45RO, HLA-Dr, CD25, and TNF-alpha monoclonal antibodies. Positively stained cells were counted and results were interpreted as cell counts/mm2.

Inhibition of cyclooxygenase 2 synthesis suppresses Herpes simplex virus type 1 reactivation.

Recurrent herpes virus infection, in which the virus reactivates from the nervous system and causes painful lesions in peripheral tissues, is a significant clinical problem. Our recent studies showing that the amount of cyclooxygenase 2 (COX-2) in the trigeminal ganglia of heat-stressed untreated mice is higher than the amount in heat-stressed mice treated with the COX-2 inhibitor, celecoxib, have indicated that the prostaglandin synthesis pathway--and in particular COX-2--may be an intermediate in the pathway to herpes viral reactivation. To further study this process, we infected the corneas of mice using topical application to a lightly scratched epithelium and waited 30 days for Herpes simplex virus type 1 (HSV-1) latency to be established in the trigeminal ganglia.

HSV-1 DNA in tears and saliva of normal adults.

Purpose: To assess the frequency of shedding of herpes simplex virus type 1 (HSV-1) DNA in tears and saliva of asymptomatic individuals.

Methods: Fifty subjects without signs of ocular herpetic disease participated. Serum samples from all subjects were tested for HSV IgG antibodies by enzyme-linked immunosorbent assay (ELISA) and for HSV-1 by neutralization assay.

Acetylsalicylic acid reduces viral shedding induced by thermal stress.

Purpose: To investigate the effect of acetylsalicylic acid on ocular shedding of herpes simplex virus type 1 (HSV-1).

Materials And Methods: Mice that were latent for the McKrae strain of HSV-1 were treated with acetylsalicylic acid, a nonspecific inhibitor of cyclooxygenases, either prophylactically or at the time of heat stress-induced viral reactivation. The effect of the drug on viral shedding in the tear film, infectious virus in the cornea and trigeminal ganglion, and viral DNA in the cornea and trigeminal ganglion was determined.

Corneal healing after uncomplicated LASIK and its relationship to refractive changes: a six-month prospective confocal study.

Purpose: To investigate corneal healing and the factor(s) possibly responsible for refractive changes after laser in situ keratomileusis (LASIK).

Methods: Twenty eyes of 10 patients who underwent LASIK for myopia were examined clinically and by real-time confocal microscopy for 6 months. Epithelial and posterior stromal thicknesses and the thickness of the keratocyte activation zone were measured, and refractive changes were compared with these values.

The comparison of efficacies of topical corticosteroids and nonsteroidal anti-inflammatory drops on dry eye patients: a clinical and immunocytochemical study.

Purpose: To investigate whether conjunctival inflammation represents a primary event in the pathogenesis of keratoconjunctivitis sicca or whether it is a secondary inflammatory reaction caused by enhanced mechanical irritation as a result of surface dryness and whether anti-inflammatory drops (corticosteroids and nonsteroidal anti-inflammatory) have therapeutic effects and are similar.

Design: Single-masked, randomized, prospective clinical trial.

Methods: Thirty-two keratoconjuctivitis patients with or without Sjögren syndrome were included in the study.

Ocular reactivation phenotype of HSV-1 strain F(MP)E, a corticosteroid-sensitive strain.

Purpose: Elucidate the ocular reactivation of HSV-1 strain F(MP)E.

Methods: Rabbit corneas were infected with HSV-1 strains McKrae and F(MP)E. Latency was established and rabbits were treated with epinephrine iontophoresis or corticosteroid injection (immunosuppression).

The effect of roscovitine on herpetic keratitis.

To determine the effect of roscovitine, a potent antiviral in tissue culture administered intramuscularly to rabbits or by eye drops to mice for the treatment of herpetic keratitis this study was commenced.New Zealand white rabbits infected with McKrae strain herpesvirus (HSV-1) were treated twice a day with 10mg Roscovitine or vehicle from day 3 to 7, or 1% trifluridine eye drops five times a day. Severity of keratitis was graded daily by a masked observer.

Confocal microscopy of Aspergillus fumigatus keratitis.

Aim: To use a confocal microscope to characterise the treated and untreated courses of fungal keratitis.

Methods: In the first experiment, Aspergillus fumigatus stromal keratitis was produced in both eyes of seven New Zealand white rabbits. In the second experiment, keratitis was induced in right eyes of 20 rabbits.

Murine keratocytes function as antigen-presenting cells.

Keratocytes express MHC class I molecules constitutively, and keratocytes stimulated with IFN-gamma express MHC class II molecules. Unstimulated keratocytes constitutively express B7-1 and ICAM-1, as well as low levels of CD40 and 4-1BBL. These findings indicate that keratocytes may deliver both antigen-specific and costimulatory signals to CD4(+) and CD8(+) T cells.

Effects of topical unoprostone and latanoprost on acute and recurrent herpetic keratitis in the rabbit.

Purpose: To determine the effect of the topical ocular hypotensive drug, isopropyl unoprostone, a docosanoid molecule with very weak prostaglandin activity, on herpes keratitis in the rabbit eye.

Methods: For acute disease, rabbit corneas inoculated with the corticosteroid-sensitive F(MP)E strain of herpes simplex virus type 1 were treated with various combinations of 0.12% isopropyl unoprostone, latanoprost, trifluridine, benzalkonium chloride 0.

Cidofovir and experimental herpetic stromal disease.

Objective: To compare topical cidofovir with topical trifluridine for the prevention and treatment of herpes simplex type 1 stromal keratitis in rabbits.

Methods: The RE strain of herpes simplex virus 1 was injected into the central stroma of both eyes of New Zealand white rabbits. Two to 3 days after virus inoculation, the rabbits were randomized to treatment groups of 10 each and treated with 1% trifluridine administered 5 or 7 times a day, 1%, 0.

Protection of corneal allografts by CTLA4-Ig.

Purpose: CTLA4, a high-affinity ligand of B7, can, in soluble form, prevent antigen-driven T-cell activation by blocking CD28-B7 interaction and can thereby prevent immune graft rejection. In this study, we tested the capacity of soluble CTLA4-Ig alone or in combination with UV-B irradiation to suppress corneal allograft rejection in rabbits.

Methods: Corneas from Dutch belted rabbits were incubated in corneal storage medium containing 0, 1, 10, 25, or 250 microg/ml of CTLA4-Ig for 18 h and were then transplanted into the vascularized or nonvascularized corneas of New Zealand White rabbit recipients.

Latanoprost increases the severity and recurrence of herpetic keratitis in the rabbit.

Purpose: To determine whether topically applied latanoprost increases the severity of acute herpes simplex keratitis, the rate of recurrence of herpes keratitis, or both, in the rabbit.

Methods: To determine the effect on severity of acute herpetic keratitis, the corneas of New Zealand white rabbits were infected with either the less-corticosteroid-sensitive McKrae strain or the corticosteroid-sensitive F(MP)E strain of herpes simplex virus type 1. Rabbits were randomly assigned to twice-a-day treatment with latanoprost 0.

Prolonged survival of corneal allografts incubated in alloantibody fragments.

Background: In this study, we determined the binding characteristics of F(ab')2 alloantibody fragments to corneal antigens and assessed the capacity of these antibody fragments to protect corneal allografts from immune attack.

Methods: Goat anti-rabbit alloantibodies were pepsin-digested and labeled with 125I, and the time course of association and dissociation of the F(ab')2 fragments was determined. Corneal allografts were incubated in unlabeled F(ab')2 fragments and transplanted into allogeneic recipients, and the graft survival times were recorded.

Trifluridine, cidofovir, and penciclovir in the treatment of experimental herpetic keratitis.

Objective: To compare trifluridine eyedrops, cidofovir eyedrops, and penciclovir ophthalmic ointment for the treatment of herpes simplex virus type 1 keratitis.

Methods: New Zealand white rabbits were infected with the McKrae strain of herpes simplex virus type 1. Three days after viral inoculation, the rabbits were randomly assigned to treatment with 1% trifluridine, 0.

A 437-base-pair deletion at the beginning of the latency-associated transcript promoter significantly reduced adrenergically induced herpes simplex virus type 1 ocular reactivation in latently infected rabbits.

In this study we used a herpes simplex virus type 1 (HSV-1) deletion mutant to identify a segment of the genome necessary for epinephrine-induced reactivation in the rabbit eye model of herpetic recurrent disease. In HSV-1 latently infected neural tissue, the only abundant viral products are the latency-associated transcripts (LATs). At least one promoter of LAT has been identified, and mutations in the LAT domain have been used to investigate HSV-1 reactivation.

Effect of 9-(4-hydroxybutyl)-N2-phenylguanine (HBPG), a thymidine kinase inhibitor, on clinical recurrences of ocular herpetic keratitis in squirrel monkeys.

9-(4-Hydroxybutyl)-N2-phenylguanine (HBPG) is a new viral thymidine kinase inhibitor that we tested for the ability to prevent recurrences of herpetic keratitis. Eighteen squirrel monkeys (Saimiri scuireus) were infected in both corneas with the Rodanus strain of herpes simplex virus type 1 (HSV-1). All corneas showed typical dendritic keratitis 3 days after infection, followed by spontaneous healing.