| Herpes keratitis (HK) is the leading cause of both cornea-derived and infection-associated blindness in the developed world. In the United States, the prevalence of HK is approximately 500,000, with the annual incidence estimated at 11.8 per 100,000 people. Clinical management of HK patients largely relies on the use of nucleoside analog antiviral drugs, which target the HSV-1 DNA polymerase enzyme. Despite the availability of effective antivirals, some patients develop refractory disease, drug-resistant infection, and topical toxicity. Multidrug-resistant HK is particularly common and serious in the growing immunocompromised population, and is confounded by the lack of therapeutic target diversity of the currently used antivirals. Novel treatment modalities may offer a unique advantage in the management of such cases. The studies outlined herein investigate the antiviral potential of interfering with virus-host interactions at the level of the DNA damage response. We demonstrate that HSV-1 infection of corneal epithelial cells results in rapid activation of ataxia telangiectasia mutated (ATM), an apical kinase in the DNA damage response. Pharmaceutical inhibition of ATM causes potent suppression of HSV-1 replication in cultured human corneal epithelial cells and in explanted human and rabbit corneas. Furthermore, ATM inhibition reduces stromal keratitis in the mouse model of HK without causing appreciable toxicity. Investigations of the underlying molecular events revealed the presence of a specialized viral mechanism, whereby the immediate early gene product ICP4 interacts with the viral genome to produce early and robust activation of ATM. This activation is shown to be independent of the presence of DNA lesions and does not appear to be mediated by the viral protein !CPO. The downstream significance of ATM activation remains to be determined. Inhibition of checkpoint kinase 2 (Chk2), a direct target of ATM, causes pronounced suppression of HSV-1 replication in corneal epithelial cells and in explanted corneas, suggesting that the pro-viral effect of ATM activation may be mediated by Chk2. These findings warrant further investigation into the DNA damage response as an area for therapeutic intervention in herpetic ocular diseases. |
