Iontophoresis (ION) is a method for administering charged drugs; application of an electrical current assures penetration of drugs into tissues. We have found that ION of 9-Beta-arabinofuranosyladenine- 5'-monophosphate (Ara-AMP) to herpes simplex virus (HSV) skin lesions in animals has superior drug efficacy compared to topical application of Ara-A, 5-iodo-2'-deoxyuridine (IDU), and Ara-AMP, ION of Ara-AMP was superior to topical application of Ara-AMP, Ara-A, and IDU for HSV keratitis. ION of Ara-AMP or 9-[2-hydroxyethoxymethyl] guanine (ACG) resulted in significant therapeutic efficacy for primary HSV stromal keratitis. HSV uveitis and stromal keratitis are ocular infections occurring beyond the corneal epithelium and they are difficult to treat. We have shown that high levels of Ara-AMP and ACG can be obtained in the anterior chamber of rabbit eyes by ION. We hope to establish that ION of Ara-AMP or ACG will have a higher therapeutic index than intravenous administraion of Ara-AMP or ACG for HSV stromal keratitis and uveitis. If these therapeutic studies are successful, the possibility exists that ION will be indicated in the application of antivirals to HSV ocular infections in humans. We have developed a model for induced HSV-1 ocular shedding by ION of epinephrine (EPI) to the corneas of HSV-1 latently infected rabbits. ION of EPI is a reliable and efficient method for inducing HSV shedding. We have analyzed the induced appearance of HSV in the rabbit tear film and know the time of the highest frequency of shedding and the highest viral titer. Since HSV-1 can be recovered from cell-free preparations of neural tissues after ION Of EPI to the cornea, we suggest that the HSV latency has been "altered." We propose to investigate the reactivated neural tissues for changes in HSV antigens and RNA. Using our reactivation model, we will monitor the rabbit eyes for the "induced" recurrence of HSV ocular lesions. Since the HSV-1 ocular shedding is induced by an adrenergic agent, we propose to pharmacologically characterize the reactivation by the use of adrenergic agonists and antagonists. If these studies are successful, the possibility exists that a treatment may become available to inhibit or reduce the reactivation of HSV.