Herpes Simplex Keratitis
The most common infectious cause of blindness in the United States, ocular herpes is a devastating and recurrent condition that can eventually scar the cornea such that corneal transplantation is necessary to restore sight. This disease is a major focus of research at the Eye Center, including pharmacological, immunological, and clinical studies under way. Because the major damage is caused by recurrences and because recurrences are the result of a virus that reactivates from dormancy in the nervous system, new types of drugs that could prevent reactivation by interfering with the biochemical processes of the virus are being tested; such a drug could be taken by high risk patients at susceptible times to prevent episodes of herpes and the damage they cause.
Immunological defenses against herpes simplex are being examined to better understand the interaction between the virus and the host and how these interactions suppress or exacerbate the disease. As an innate response to virus infection, most cells produce interferon-α, -β, or -γ. Dr. Bryan Gebhardt has found that T cell-derived interferon-γ, working in synergy with interferon-α and -β, can dramatically inhibit replication of herpes simplex virus. The effects were similar to those seen with acyclovir, the current systemic drug of choice in the treatment of clinical herpes. Further work by this collaborative has led to the targeting of ICP-0 (intracellular binding protein). Future investigations will focus on the development of a therapeutic vaccine with minimal systemic toxicity to be used either as an external drug therapy or a protein-targeting agent to elicit the interferon response.
Repeated inflammation in the corneal stroma can lead to herpetic stromal keratitis, an immune inflammatory process that results in blindness. Dr. Byoung Kwon, in collaboration with Drs. Bryan Gebhardt, James Hill and Herbert Kaufman, is investigating the effect of modulating T-cell costimulation on herpetic stromal keratitis and acute and latent herpes infection. These studies will aid in understanding the immunological mechanisms involved in herpetic stromal keratitis and allow the development of treatments for this and other ocular inflammatory diseases.
In order to develop effective therapies to treat herpes simplex eye disease, the molecular mechanisms that trigger recurrence of the disease must be elucidated. Dr. Herbert Kaufman, in collaboration with Drs. Bryan Gebhardt, James Hill and Nicolas Bazan, is working to uncover new approaches to treatment of this disease by identifying the intracellular processes that enable viral reactivation from latency in the neuron and takeover of cellular metabolism for viral reproduction. Dr. Herbert Kaufman’s work has revealed a very promising target for recurrence: the cyclooxygenase-2 (COX-2) gene. Current work in in vivo models focuses on the effects of COX-2 inhibitors, including Celecoxib and a proprietary selective COX-2 inhibitor, on viral reactivation.
Molecular studies of the role of specific genetic sequences in herpes simplex virus DNA using epinephrine, immunosuppression, and hyperthermia models of rabbit reactivation and recurrent disease are in progress in Dr. James Hill’s laboratories. Using genetically engineered viruses altered in specific regions involved in RNA infection, latency, and reactivation, Dr. Hill and his collaborators are identifying specific regions of the viral DNA critical for blocking the reactivation of the herpes virus and preventing recurrence of the disease.