Purchase this article with an account.
Oleg Alekseev, Kelly Donovan, Jane Azizkhan-Clifford; ATM Activation by HSV-1: a Critical and Targetable Step in Herpes Simplex Keratitis. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1691.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Herpes keratitis (HK) remains the leading cause of cornea-derived blindness in the developed world, despite the availability of effective antiviral drugs. Treatment toxicity and the emergence of drug resistance highlight the need for additional therapeutic approaches. We examined ataxia telangiectasia mutated (ATM), an apical kinase in the host DNA damage response, as a potential new target for the treatment of HK.
Small molecule inhibitor of ATM (KU-55933) was used to treat HSV-1 infection in cultured human corneal epithelial cells, explanted human and rabbit corneas, and in mice. Infection productivity was assayed by plaque assay, real time PCR, Western blot, and disease scoring. Mechanistic studies relied on mutant viral strains, bacterial artificial chromosomes, and comet assays.
Robust and early ATM activation was detected in HSV-1-infected human corneal epithelial cells. Inhibition of ATM greatly suppressed viral replication in cultured cells and in explanted human and rabbit corneas, and reduced the severity of stromal keratitis in mice. The antiviral effect of KU-55933 in combination with acyclovir was additive, and KU-55933 suppressed replication of a drug-resistant HSV-1 strain. KU-55933 caused minimal toxicity, as monitored by clonogenic survival assay and fluorescein staining. Mechanistic studies show that ATM activation during HSV-1 infection occurs in the absence of DNA damage and is independent of viral genome replication, tegument proteins alone, or ICP0. Results of further investigations into the mechanisms behind ATM activation and its downstream significance will also be presented.
This study identifies ATM as a potential target for the treatment of HK and delves into the mechanisms underlying its involvement. ATM inhibition by KU-55933 reduces epithelial infection and stromal disease severity without producing appreciable toxicity. Additional experiments reveal a potential mechanistic model of ATM activation and subsequent significance in HSV-1 infection.
This PDF is available to Subscribers Only