The percentage of asymptomatic subjects who intermittently shed HSV-1 DNA in tears or saliva was higher than the percentage of subjects with positive ELISA or neutralization antibodies to HSV. Because most HSV transmission occurs during asymptomatic shedding, further knowledge of the prevalence of HSV-1 DNA in tears and saliva is warranted to control its spread. Shedding is simple to study, and its suppression may be an efficient way to evaluate new antivirals in humans.

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. Neuronal latency in the peripheral ganglia is established when transcription of the viral genome is repressed (silenced) except for the latency-associated transcripts and microRNAs. The functions of latency-associated transcripts have been investigated since 1987. Roles have been suggested relating to reactivation, establishment of latency, neuronal protection, antiapoptosis, apoptosis, virulence and asymptomatic shedding. Here, we review HSV-1 latent infections, reactivation, recurrent disease and antiviral therapies for the ocular HSV diseases.

No abstract

No abstract

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. Prior to the induction of viral reactivation, the mice were treated orally with celecoxib. Treated and untreated mice were induced to undergo reactivation by immersion in 43 degrees C water for 10 min. The shedding of virus at the ocular surface was determined by culturing ocular swabs with indicator cells. The presence of infectious virus in the trigeminal ganglion was evaluated by incubating ganglion homogenates with indicator cells and observing for cytopathic effect. Celecoxib treatment significantly suppressed viral reactivation when given prophylactically by the gastrointestinal route. The numbers of corneas and ganglia containing infectious virus were significantly lower in the celecoxib-treated animals, compared to the placebo-treated mice. These experiments demonstrate that a selective COX-2 inhibitor can suppress hyperthermic stress-induced herpes viral reactivation in the nervous system. It may be possible to use COX-2 inhibitors to prevent viral reactivation in high-risk patients by drug prophylaxis.

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. Group 1 (n = 14) received the placebo, group 2 (n = 15) received a dose of 500 mg valacyclovir once daily, and group 3 (n = 16) received a dose of 500 mg valacyclovir once daily and 350 mg aspirin twice daily for 30 days. Ocular and oral swabs were collected twice daily for 30 days. DNA was extracted from all swabs and HSV-1 DNA copy numbers were determined. Statistical analysis was performed to compare the DNA copy numbers of the three groups. Results There was no significant difference in the HSV-1 DNA copy numbers in the tears or saliva among any of the three treatment groups. The mean copy numbers ± SE of mean (SEM) of HSV-1 DNA in tears were 340 ± 35, 1074 ± 320, and 630 ± 51 for groups 1, 2, and 3, and in saliva were 238 ± 35, 963 ± 462, and 493 ± 25, respectively, for groups 1, 2, and 3. Conclusions No correlation was found between HSV-1 shedding and valacyclovir and valacyclovir with aspirin treatment. The HSV-1 DNA copy number was not reduced by treatment with 500 mg of valacyclovir daily or with a combination of daily valacyclovir (500 mg) plus twice-daily doses of aspirin (350 mg) over 30 days.

No abstract

For patients with conditions requiring chronic rather than acute therapy, the advantages of collagen shields in providing high and sustained levels of drugs and/or lubricants to the cornea are outweighed by the difficulty of insertion of the shield and the problem of blurred vision. We have developed a delivery system in which collagen pieces suspended in a viscous vehicle can be instilled into the lower forniceal space, thereby simplifying application and reducing blurring of vision. The collagen pieces (Collasomes) can be formulated with various constituents such as antibiotics or cyclosporine, or with chemical alterations such as the inclusion of a lipid (Lacrisomes) for the treatment of dry eyes. In the normal eyes of volunteers, Collasomes hydrated in a solution of sodium fluorescein and suspended in a methylcellulose vehicle as a model for delivery of water-soluble drugs produced fluorescein concentrations 17 to 42 times higher in the cornea and 6 to 8 times higher in the aqueous humor, compared with fluorescein-containing vehicle alone. In a preliminary controlled study, 76% of patients with moderately severe keratoconjunctivitis sicca (KCS) preferred Lacrisomes to the vehicle control because of a more soothing effect and longer duration of comfort. All preparations were well tolerated by all study subjects. Current studies involve improving drug delivery by chemically modifying the collagen molecule to slow diffusion of the drug from the Collasome matrix, as well as varying the amount of cetyl alcohol and combining it with modified collagen in Lacrisomes to maximize comfort in patients with dry eyes.